A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of
chemical reactions
A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breaking ...
that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that is
transduced to the cell interior through second messengers which amplify the signal and transfer it to effector molecules, causing the cell to respond to the initial stimulus.
Most biochemical cascades are series of events, in which one event triggers the next, in a linear fashion. At each step of the signaling cascade, various controlling factors are involved to regulate cellular actions, in order to respond effectively to cues about their changing internal and external environments.
An example would be the
coagulation cascade
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
of secondary
hemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, whi ...
which leads to
fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...
formation, and thus, the initiation of blood coagulation. Another example,
sonic
Sonic or Sonics may refer to:
Companies
*Sonic Drive-In, an American drive-in fast-food restaurant chain
*Sonic (ISP), an Internet provider and CLEC, serving more than 100 California communities
*Sonic Foundry, a computer software company whic ...
hedgehog signaling pathway
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathwa ...
, is one of the key regulators of
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
and is present in all
bilaterians
The Bilateria or bilaterians are animals with bilateral symmetry as an embryo, i.e. having a left and a right side that are mirror images of each other. This also means they have a head and a tail (anterior-posterior axis) as well as a belly and ...
.
Signaling proteins give cells information to make the embryo develop properly. When the pathway malfunctions, it can result in diseases like
basal cell carcinoma
Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
.
Recent studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. The pathway has also been implicated in the development of some cancers. Drugs that specifically target hedgehog signaling to fight diseases are being actively developed by a number of pharmaceutical companies.
Introduction
Signaling cascades
Cells require a full and functional cellular machinery to live. When they belong to complex multicellular organisms, they need to communicate among themselves and work for symbiosis in order to give life to the organism. These communications between cells triggers intracellular signaling cascades, termed
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
pathways, that regulate specific cellular functions. Each signal transduction occurs with a primary extracellular messenger that binds to a transmembrane or nuclear receptor, initiating intracellular signals. The complex formed produces or releases second messengers that integrate and adapt the signal, amplifying it, by activating molecular targets, which in turn trigger effectors that will lead to the desired cellular response.
Transductors and effectors
Signal transduction is realized by activation of specific receptors and consequent production/delivery of second messengers, such as Ca
2+ or
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
. These molecules operate as signal transducers, triggering intracellular cascades and in turn amplifying the initial signal.
Two main signal transduction mechanisms have been identified, via
nuclear receptors
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of specif ...
, or via transmembrane receptors. In the first one, first messenger cross through the cell membrane, binding and activating intracellular receptors localized at nucleus or
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
, which then act as
transcriptional factors regulating directly gene expression. This is possible due to the lipophilic nature of those ligands, mainly hormones. In the signal transduction via transmembrane receptors, the first messenger binds to the extracellular domain of transmembrane receptor, activating it. These receptors may have intrinsic catalytic activity or may be coupled to effector enzymes, or may also be associated to ionic channels. Therefore, there are four main transmembrane receptor types:
G protein coupled receptors
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
(GPCRs),
tyrosine kinase receptors
Receptor tyrosine kinases (RTKs) are the high-dissociation constant#Protein-ligand binding, affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the hu ...
(RTKs),
serine/threonine kinase receptor
A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human protei ...
s (RSTKs), and
ligand-gated ion channels
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...
(LGICs).
Second messengers can be classified into three classes:
# Hydrophilic/cytosolic – are soluble in water and are localized at the cytosol, including cAMP,
cGMP,
IP3, Ca
2+,
cADPR
Cyclic ADP Ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like cAMP) with two phosphate groups present on 5' OH of the adenosine (like ADP), further connected to another ribose at the 5' position, which, in turn, closes t ...
and
S1P. Their main targets are protein kinases as
PKA and
PKG, being then involved in phosphorylation mediated responses.
# Hydrophobic/membrane-associated – are insoluble in water and membrane-associated, being localized at intermembrane spaces, where they can bind to membrane-associated effector proteins. Examples:
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid th ...
,
DAG,
phosphatidic acid Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty ac ...
,
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
and
ceramide
Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetylsphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up ...
. They are involved in regulation of kinases and phosphatases, G protein associated factors and transcriptional factors.
# Gaseous – can be widespread through cell membrane and cytosol, including
nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
and
carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
. Both of them can activate cGMP and, besides of being capable of mediating independent activities, they also can operate in a coordinated mode.
Cellular response
The cellular response in signal transduction cascades involves alteration of the expression of effector genes or activation/inhibition of targeted proteins. Regulation of protein activity mainly involves phosphorylation/dephosphorylation events, leading to its activation or inhibition. It is the case for the vast majority of responses as a consequence of the binding of the primary messengers to membrane receptors. This response is quick, as it involves regulation of molecules that are already present in the cell. On the other hand, the induction or repression of the expression of genes requires the binding of
transcriptional factors to the
regulatory sequences
A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and vir ...
of these genes. The transcriptional factors are activated by the primary messengers, in most cases, due to their function as nuclear receptors for these messengers. The
secondary messengers
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
like
DAG or Ca
2+ could also induce or repress gene expression, via transcriptional factors. This response is slower than the first because it involves more steps, like transcription of genes and then the effect of newly formed proteins in a specific target. The target could be a protein or another gene.
Examples of biochemical cascades
In
biochemistry
Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
, several important
enzymatic
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
cascades and
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
cascades participate in
metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
s or signaling networks, in which enzymes are usually involved to
catalyze
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the reactions. For example, the tissue factor pathway in the
coagulation cascade
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
of secondary
hemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, whi ...
is the primary pathway leading to
fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...
formation, and thus, the initiation of blood coagulation. The pathways are a series of reactions, in which a
zymogen
In biochemistry, a zymogen (), also called a proenzyme (), is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the active ...
(inactive enzyme precursor) of a
serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
and its
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
co-factors are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked
fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...
.
Another example,
sonic
Sonic or Sonics may refer to:
Companies
*Sonic Drive-In, an American drive-in fast-food restaurant chain
*Sonic (ISP), an Internet provider and CLEC, serving more than 100 California communities
*Sonic Foundry, a computer software company whic ...
hedgehog signaling pathway
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathwa ...
, is one of the key regulators of
embryonic development
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
and is present in all
bilaterians
The Bilateria or bilaterians are animals with bilateral symmetry as an embryo, i.e. having a left and a right side that are mirror images of each other. This also means they have a head and a tail (anterior-posterior axis) as well as a belly and ...
.
Different parts of the embryo have different concentrations of hedgehog signaling proteins, which give cells information to make the embryo develop properly and correctly into a head or a tail. When the pathway malfunctions, it can result in diseases like
basal cell carcinoma
Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
.
[Antoniotti, M., Park, F., Policriti, A., Ugel, N., Mishra, B. (2003) Foundations of a query and simulation system for the modeling of biochemical and biological processes. In Pacific Symposium on Biocomputing 2003 (PSB 2003), pp. 116–127.] Recent studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. The pathway has also been implicated in the development of some cancers. Drugs that specifically target hedgehog signaling to fight diseases are being actively developed by a number of pharmaceutical companies. Most biochemical cascades are series of events, in which one event triggers the next, in a linear fashion.
Biochemical cascades include:
*The
Complement system
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
*The
Insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
Signaling Pathway
*The
Sonic hedgehog
Sonic hedgehog protein (SHH) is encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog''.
This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and ...
Signaling Pathway
*The
Wnt signaling pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...
*The
JAK-STAT
The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals out ...
signaling pathway
*The
Adrenergic receptor
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
Pathways
*The
Acetylcholine receptor
An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
Classification
Like other transmembrane receptors, acetylcholine receptors are classified according ...
Pathways
*The
Mitogen-activated protein kinase
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
cascade
Conversely, negative cascades include events that are in a circular fashion, or can cause or be caused by multiple events. Negative cascades include:
*
Ischemic cascade
The ischemic (ischaemic) cascade is a series of biochemical reactions that are initiated in the brain and other aerobic tissues after seconds to minutes of ischemia (inadequate blood supply). This is typically secondary to stroke, injury, or card ...
Cell-specific biochemical cascades
Epithelial cells
Adhesion
Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another).
The forces that cause adhesion and cohesion can be ...
is an essential process to epithelial cells so that epithelium can be formed and cells can be in permanent contact with extracellular matrix and other cells. Several pathways exist to accomplish this communication and adhesion with environment. But the main signalling pathways are the cadherin and integrin pathways.
The
cadherin
Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane proteins, ...
pathway is present in adhesion junctions or in desmosomes and it is responsible for epithelial adhesion and communication with adjacent cells. Cadherin is a transmembrane glycoprotein receptor that establishes contact with another cadherin present in the surface of a neighbour cell forming an adhesion complex. This adhesion complex is formed by
β-catenin
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcriptio ...
and
α-catenin
Alpha-catenin functions as the primary protein link between cadherins and the actin cytoskeleton. It has been reported that the actin binding proteins vinculin and alpha-actinin can bind to alpha-catenin. It has been suggested that alpha-caten ...
, and p120
CAS is essential for its stabilization and regulation. This complex then binds to
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
, leading to polymerization. For actin polymerization through the cadherin pathway, proteins of the
Rho GTPases family are also involved. This complex is regulated by phosphorylation, which leads to downregulation of adhesion. Several factors can induce the phosphorylation, like
EGF,
HGF or
v-Src
v-Src is a gene found in Rous sarcoma virus (RSV) that encodes a tyrosine kinase that causes a type of cancer in chickens.
The src gene is oncogenic as it triggers uncontrolled growth in abnormal host cells. It was the first retroviral oncogene ...
. The cadherin pathway also has an important function in survival and proliferation because it regulates the concentration of cytoplasmic β-catenin. When β-catenin is free in the cytoplasm, normally it is degraded, however if the
Wnt signalling is activated, β-catenin degradation is inhibited and it is translocated to the nucleus where it forms a complex with transcription factors. This leads to activation of genes responsible for cell proliferation and survival. So the cadherin-catenin complex is essential for cell fate regulation.
Integrins
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
are heterodimeric glycoprotein receptors that recognize proteins present in the extracellular matrix, like fibronectin and laminin. In order to function, integrins have to form complexes with
ILK
Integrin-linked kinase is an enzyme that in humans is encoded by the ILK gene involved with integrin-mediated signal transduction. Mutations in ''ILK'' are associated with cardiomyopathies. It is a 59kDa protein originally identified in a yeast-two ...
and
Fak proteins. For adhesion to the extracellular matrix, ILK activate the
Rac
RAC or Rac may refer to:
Organizations
* Radio Amateurs of Canada
* RATCH-Australia Corporation, electricity generator
* Refugee Action Collective (Victoria), Melbourne, Australia
* Religious Action Center of Reform Judaism, US
* Rent-A-Center, ...
and
Cdc42 proteins and leading to actin polymerization. ERK also leads to actin polymerization through activation of
cPLA2. Recruitment of FAK by integrin leads to
Akt
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
activation and this inhibits pro-apoptotic factors like BAD and Bax. When adhesion through integrins do not occur the pro-apoptotic factors are not inhibited and resulting in
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
Hepatocytes
The
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
is a complex and multifunctional differentiated cell whose cell response will be influenced by the zone in
hepatic lobule
In histology (microscopic anatomy), the lobules of liver, or hepatic lobules, are small divisions of the liver defined at the microscopic scale. The hepatic lobule is a building block of the liver tissue, consisting of a portal triad, hepatocyte ...
, because concentrations of oxygen and toxic substances present in the hepatic sinusoids change from periportal zone to centrilobular zone10. The hepatocytes of the intermediate zone have the appropriate morphological and functional features since they have the environment with average concentrations of oxygen and other substances.
This specialized cell is capable of:
* Regulate
glucose metabolism
Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.
Carbohydrates are central to many essential metabolic pathways. Plants ...
# Via
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
/
PKA/TORC (transducers of regulated CREB)/
CRE,
PIP3
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid th ...
/
PKB PKB is a three-letter abbreviation that may refer to:
* Państwowy Korpus Bezpieczeństwa, WWII Polish underground police
* Patients Know Best, a tool for allowing the patient to share medical records with clinicians
* National Awakening Party (''P ...
and
PLC /
IP3
# Expression of enzymes for synthesis, storage and distribution of glucose
* Synthesis of
acute phase proteins
# Via
JAK
Jak may refer to:
Places
* Ják, a village in Hungary
People
* Jak Alnwick (born 1993), English football goalkeeper
* Jak Jones (born 1993), Welsh professional snooker player
* Raymond Jackson ("JAK") (1927–1997), UK cartoonist
* Jak Airport ( ...
/
STAT
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
/APRE (acute phase response element)
# Expression of C-reactive protein, globulin protease inhibitors, complement, coagulation and fibrinolytic systems and iron homeostasis
*
Regulate iron homeostasis (acute phase independent)
# Via
Smads /
HAMP
Hepcidin is a protein that in humans is encoded by the ''HAMP'' gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.
During conditions in which the hepcidin level is abnormally high, such as inflammation, se ...
#
Hepcidin
Hepcidin is a protein that in humans is encoded by the ''HAMP'' gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.
During conditions in which the hepcidin level is abnormally high, such as inflammation, se ...
expression
* Regulate
lipid metabolism
Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...
# Via
LXR /LXRE (LXR response element)
# Expression of
ApoE
Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease.
APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
CETP
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-de ...
,
FAS and
LPL
* Exocrine production of
bile salts
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Primary b ...
and other compounds
# Via
LXR /LXRE
# Expression of
CYP7A1
Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enz ...
and
ABC transporters
The ATP synthase, ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene family, gene families. It is represented in all extant taxon, extant Phylum ...
* Degradate of toxic substances
# Via
LXR /LXRE
# Expression of
ABC transporters
The ATP synthase, ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene family, gene families. It is represented in all extant taxon, extant Phylum ...
* Endocrine production
# Via
JAK
Jak may refer to:
Places
* Ják, a village in Hungary
People
* Jak Alnwick (born 1993), English football goalkeeper
* Jak Jones (born 1993), Welsh professional snooker player
* Raymond Jackson ("JAK") (1927–1997), UK cartoonist
* Jak Airport ( ...
/
STAT
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
/GHRE (growth hormone response element)
:
IGF-1
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.
IGF-1 is a protein that in humans is ...
and
IGFBP-3
Insulin-like growth factor-binding protein 3, also known as IGFBP-3, is a protein that in humans is encoded by the ''IGFBP3'' gene. IGFBP-3 is one of six IGF binding proteins ( IGFBP-1 to IGFBP-6) that have highly conserved structures and bind th ...
expression
# Via
THR/THRE (thyroid hormone response element)
:
Angiotensinogen
Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adren ...
expression
* Regenerate itself by hepatocyte mitosis
# Via
STAT
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
and
Gab1
GRB2-associated-binding protein 1 is a protein that in humans is encoded by the ''GAB1'' gene.
Function
The protein encoded by this gene is a member of the IRS1-like multisubstrate docking protein family. The encoded protein is an important me ...
:
RAS
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
/
MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
,
PLC/
IP3 and
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
/
FAK
# Cell growth, proliferation, survival, invasion and motility
The hepatocyte also regulates other functions for constitutive synthesis of proteins (
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
,
ALT
Alt or ALT may refer to:
Abbreviations for words
* Alt account, an alternative online identity also known as a sock puppet account
* Alternate character, in online gaming
* Alternate route, type of highway designation
* Alternating group, mathema ...
and
AST) that influences the synthesis or activation of other molecules (synthesis of urea and essential amino acids), activate
vitamin D
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...
, utilization of
vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
, transporter expression of
vitamin A
Vitamin A is a fat-soluble vitamin and an essential nutrient for humans. It is a group of organic compounds that includes retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin A carotenoids (most notably bet ...
and conversion of
thyroxine
File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4
rect 376 268 820 433 Thyroid-stimulating hormone
rect 411 200 849 266 Thyrotropin-releasing hormone
rect 297 168 502 200 Hypothalamus
rect 66 216 386 25 ...
.
Neurons
Purinergic signalling
Purinergic signalling (or signaling: see American and British English differences) is a form of extracellular signalling mediated by purine nucleotides and nucleosides such as adenosine and ATP. It involves the activation of purinergic recept ...
has an essential role at interactions between neurons and
glia cells
Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...
, allowing these to detect
action potentials
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, c ...
and modulate neuronal activity, contributing for intra and extracellular homeostasis regulation. Besides purinergic neurotransmitter, ATP acts as a trophic factor at cellular development and growth, being involved on microglia activation and migration, and also on axonal myelination by oligodendrocytes. There are two main types of
purinergic receptors
Purinergic receptors, also known as purinoceptors, are a family of plasma membrane molecules that are found in almost all mammalian tissues. Within the field of purinergic signalling, these receptors have been implicated in learning and memory, l ...
, P1 binding to
adenosine
Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
, and P2 binding to ATP or ADP, presenting different signalling cascades.
The
Nrf2
Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may reg ...
/ARE signalling pathway has a fundamental role at fighting against oxidative stress, to which neurons are especially vulnerable due to its high oxygen consumption and high lipid content. This neuroprotective pathway involves control of neuronal activity by perisynaptic astrocytes and neuronal glutamate release, with the establishment of tripartite synapses. The Nrf2/ARE activation leads to a higher expression of enzymes involved in glutathione syntheses and metabolism, that have a key role in antioxidant response.
The LKB1/NUAK1 signalling pathway regulates terminal axon branching at cortical neurons, via local immobilized mitochondria capture. Besides
NUAK1, LKB1 kinase acts under other effectors enzymes as SAD-A/B and MARK, therefore regulating neuronal polarization and axonal growth, respectively. These kinase cascades implicates also Tau and others
MAP
A map is a symbolic depiction emphasizing relationships between elements of some space, such as objects, regions, or themes.
Many maps are static, fixed to paper or some other durable medium, while others are dynamic or interactive. Although ...
.
An extended knowledge of these and others neuronal pathways could provide new potential therapeutic targets for several neurodegenerative chronic diseases as
Alzheimer's
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
,
Parkinson's
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
and
Huntington's
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
disease, and also
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
.
Blood cells
The
blood cells
A blood cell, also called a hematopoietic cell, hemocyte, or hematocyte, is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), a ...
(
erythrocytes
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
,
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
and
platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
) are produced by
hematopoiesis
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...
.
The
erythrocytes
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
have as main function the O
2 delivery to the tissues, and this transfer occurs by diffusion and is determined by the O
2 tension (PO
2). The erythrocyte is able to feel the tissue need for O
2 and cause a change in vascular caliber, through the pathway of
ATP release, which requires an increase in
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
, and are regulated by the
phosphodiesterase
A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...
(PDE). This pathway can be triggered via two mechanisms: physiological stimulus (like reduced O2 tension) and activation of the
prostacyclin receptor
The Prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, ...
(IPR). This pathway includes heterotrimeric
G proteins
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
,
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
(AC),
protein kinase A
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
(PKA),
cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wit ...
(CFTR), and a final conduit that transport ATP to vascular lumen (
pannexin 1 or
voltage-dependent anion channel
Voltage-dependent anion channels, or mitochondrial porins, are a class of porin ion channel located on the outer mitochondrial membrane. There is debate as to whether or not this channel is expressed in the cell surface membrane.
This major pro ...
(VDAC)). The released ATP acts on
purinergic receptors
Purinergic receptors, also known as purinoceptors, are a family of plasma membrane molecules that are found in almost all mammalian tissues. Within the field of purinergic signalling, these receptors have been implicated in learning and memory, l ...
on endothelial cells, triggering the synthesis and release of several
vasodilators
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
, like nitric oxide (NO) and prostacyclin (PGI
2).
The current model of
leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
adhesion cascade includes many steps mentioned in Table 1. The
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
-mediated adhesion of
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
to
endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
is related with morphological changes in both leukocytes and endothelial cells, which together support leukocyte migration through the venular walls.
Rho
Rho (uppercase Ρ, lowercase ρ or ; el, ρο or el, ρω, label=none) is the 17th letter of the Greek alphabet. In the system of Greek numerals it has a value of 100. It is derived from Phoenician letter res . Its uppercase form uses the sa ...
and
Ras
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
small GTPases
Small GTPases (), also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotr ...
are involved in the principal leukocyte signaling pathways underlying
chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
-stimulated
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
-dependent adhesion, and have important roles in regulating cell shape, adhesion and motility.
![Leukocyte adhesion cascade](https://upload.wikimedia.org/wikipedia/commons/b/b1/Leukocyte_adhesion_cascade.JPG)
After a vascular injury occurs,
platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
are activated by locally exposed
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
(glycoprotein (GP) VI receptor), locally generated
thrombin
Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
(PAR1 and PAR4 receptors), platelet-derived
thromboxane A2
Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by act ...
(TxA2) (TP receptor) and ADP (P2Y1 and P2Y12 receptors) that is either released from damaged cells or secreted from
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
dense granules. The
von Willebrand factor
Von Willebrand factor (VWF) () is a blood glycoprotein involved in hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytopen ...
(VWF) serves as an essential accessory molecule. In general terms,
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
activation initiated by agonist takes to a signaling cascade that leads to an increase of the cytosolic calcium concentration. Consequently, the
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
α
IIbβ
3 is activated and the binding to
fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clo ...
allows the aggregation of
platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
to each other. The increase of cytosolic calcium also leads to shape change and TxA2 synthesis, leading to signal amplification.
Lymphocytes
The main goal of biochemical cascades in
lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
is the secretion of molecules that can suppress altered cells or eliminate pathogenic agents, through proliferation, differentiation and activation of these cells. Therefore, the antigenic receptors play a central role in signal transduction in lymphocytes, because when antigens interact with them lead to a cascade of signal events. These receptors, that recognize the antigen soluble (B cells) or linked to a molecule on
Antigen Presenting Cells
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
(T cells), do not have long cytoplasm tails, so they are anchored to signal proteins, which contain a long cytoplasmic tails with a motif that can be phosphorylated (
ITAM – immunoreceptor tyrosine-based activation motif) and resulting in different signal pathways. The
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
receptor and signal protein form a stable complex, named
BCR or
TCR, in B or T cells, respectively. The family
Src is essential for signal transduction in these cells, because it is responsible for phosphorylation of ITAMs. Therefore,
Lyn and
Lck
Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...
, in lymphocytes B and T, respectively, phosphorylate
immunoreceptor tyrosine-based activation motif An immunoreceptor tyrosine-based activation motif (ITAM) is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of non-catalytic tyrosine-phosphorylated receptors, cell-surface proteins found mainly on immune cel ...
s after the antigen recognition and the conformational change of the receptor, which leads to the binding of
Syk
Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene.
Function
SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
/
Zap-70
ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding t ...
kinases to ITAM and its activation.
Syk
Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the ''SYK'' gene.
Function
SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. These cytoplasmic non-receptor t ...
kinase is specific of lymphocytes B and
Zap-70
ZAP-70 (Zeta-chain-associated protein kinase 70) is a protein normally expressed near the surface membrane of lymphocytes (T cells, natural killer cells, and a subset of B cells). It is most prominently known to be recruited upon antigen binding t ...
is present in T cells. After activation of these enzymes, some adaptor proteins are phosphorylated, like
BLNK (B cells) and
LAT
Lat or LAT may refer to:
Places
* Lat, Fuman, village in Gilan Province, Iran
* Lat, Rasht, village in Gilan Province, Iran
* Lat, Mazandaran, village in Iran
* Lat-e Disar, village in Mazandaran Province, Iran
* Lat, Qazvin, village in I ...
(T cells). These proteins after phosphorylation become activated and allow binding of others enzymes that continue the biochemical cascade.
One example of a protein that binds to adaptor proteins and become activated is PLC that is very important in the lymphocyte signal pathways.
PLC is responsible for
PKC activation, via
DAG and Ca
2+, which leads to phosphorylation of
CARMA1 molecule, and formation of CBM complex. This complex activates Iκκ kinase, which phosphorylates I-κB, and then allows the translocation of
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
to the nucleus and transcription of genes encoding
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
, for example. Others transcriptional factors like
NFAT
Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the developme ...
and
AP1 complex are also important for transcription of
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
.
The differentiation of B cells to
plasma cells
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
is also an example of a signal mechanism in lymphocytes, induced by a
cytokine receptor
Cytokine receptors are receptors that bind to cytokines.
In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly bec ...
. In this case, some
interleukins
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and relate ...
bind to a specific receptor, which leads to activation of
MAPK/ERK pathway
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
The signal starts when a signaling ...
. Consequently, the
BLIMP1 protein is translated and inhibits
PAX5
Paired box protein Pax-5 is a protein that in humans is encoded by the ''PAX5'' gene.
Function
The PAX5 gene is a member of the paired box (PAX) family of transcription factors. The central feature of this gene family is a novel, highly cons ...
, allowing immunoglobulin genes transcription and activation of
XBP1
X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the ''XBP1'' gene. The ''XBP1'' gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5. The XBP ...
(important for the secretory apparatus formation and enhancing of protein synthesis). Also, the coreceptors (
CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provid ...
/
CD19
B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In humans, ...
) play an important role because they can improve the antigen/receptor binding and initiate parallel cascade events, like activation o PI3 Kinase. PIP3 then is responsible for activation of several proteins, like
vav (leads to activation of
JNK
c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and ar ...
pathway, which consequently leads to activation of
c-Jun
Transcription factor Jun is a protein that in humans is encoded by the ''JUN'' gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only lat ...
) and
btk (can also activate PLC).
Bones
Wnt signaling pathway
The
Wnt signaling pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...
can be divided in canonical and non-canonical. The canonical signaling involves binding of Wnt to Frizzled and LRP5 co-receptor, leading to GSK3 phosphorylation and inhibition of β-catenin degradation, resulting in its accumulation and translocation to the nucleus, where it acts as a transcription factor. The non-canonical Wnt signaling can be divided in planar cell polarity (PCP) pathway and Wnt/calcium pathway. It is characterized by binding of Wnt to Frizzled and activation of G proteins and to an increase of intracellular levels of calcium through mechanisms involving PKC 50. The Wnt signaling pathway plays a significative role in osteoblastogenesis and bone formation, inducing the differentiation of mesenquimal pluripotent cells in osteoblasts and inhibiting the RANKL/RANK pathway and osteoclastogenesis.
RANKL/RANK signaling pathway
RANKL is a member of the TNF superfamily of ligands. Through binding to the RANK receptor it activates various molecules, like NF-kappa B, MAPK, NFAT and PI3K52. The RANKL/RANK signaling pathway regulates osteoclastogenesis, as well as, the survival and activation of osteoclasts.
Adenosine signaling pathway
Adenosine is very relevant in bone metabolism, as it plays a role in formation and activation of both osteoclasts and osteoblasts. Adenosine acts by binding to purinergic receptors and influencing adenylyl cyclase activity and the formation of cAMP and PKA 54.
Adenosine may have opposite effects on bone metabolism, because while certain purinergic receptors stimulate adenylyl cyclase activity, others have the opposite effect.
Under certain circumstances adenosine stimulates bone destruction and in other situations it promotes bone formation, depending on the purinergic receptor that is being activated.
Stem cells
Self-renewal and differentiation abilities are exceptional properties of stem cells. These cells can be classified by their differentiation capacity, which progressively decrease with development, in totipotents, pluripotents, multipotents and unipotents.
Self-renewal process is highly regulated from cell cycle and genetic transcription control. There are some signaling pathways, such as
LIF
Lithium fluoride is an inorganic compound with the chemical formula LiF. It is a colorless solid, that transitions to white with decreasing crystal size. Although odorless, lithium fluoride has a bitter-saline taste. Its structure is analogous to ...
/
JAK
Jak may refer to:
Places
* Ják, a village in Hungary
People
* Jak Alnwick (born 1993), English football goalkeeper
* Jak Jones (born 1993), Welsh professional snooker player
* Raymond Jackson ("JAK") (1927–1997), UK cartoonist
* Jak Airport ( ...
/
STAT3
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family.
Function
STAT3 is a member of the STAT protein family. In respons ...
(Leukemia inhibitory factor/Janus kinase/Signal transducer and activator of transcription 3) and
BMP/
SMADs/Id (Bone morphogenetic proteins/ Mothers against decapentaplegic/ Inhibitor of differentiation), mediated by transcription factors, epigenetic regulators and others components, and they are responsible for self-renewal genes expression and inhibition of differentiation genes expression, respectively.
At cell cycle level there is an increase of complexity of the mechanisms in somatic stem cells. However, it is observed a decrease of self-renewal potential with age. These mechanisms are regulated by
p16Ink4a-CDK4/6-
Rb and
p19Arf-
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
-
P21
p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...
Cip1 signaling pathways. Embryonic stem cells have constitutive cyclin E-CDK2 activity, which hyperphosphorylates and inactivates Rb. This leads to a short G1 phase of the cell cycle with rapid G1-S transition and little dependence on mitogenic signals or D cyclins for S phase entry. In fetal stem cells, mitogens promote a relatively rapid G1-S transition through cooperative action of cyclin D-CDK4/6 and cyclin E-CDK2 to inactivate Rb family proteins. p16
Ink4a and p19
Arf expression are inhibited by Hmga2-dependent chromatin regulation. Many young adult stem cells are quiescent most of the time. In the absence of mitogenic signals, cyclin-CDKs and the G1-S transition are suppressed by cell cycle inhibitors including Ink4 and Cip/Kip family proteins. As a result, Rb is hypophosphorylated and inhibits E2F, promoting quiescence in G0-phase of the cell cycle. Mitogen stimulation mobilizes these cells into cycle by activating cyclin D expression. In old adult stem cells,
let-7 microRNA expression increases, reducing Hmga2 levels and increasing p16
Ink4a and p19
Arf levels. This reduces the sensitivity of stem cells to mitogenic signals by inhibiting cyclin-CDK complexes. As a result, either stem cells cannot enter the cell cycle, or cell division slows in many tissues.
Extrinsic regulation is made by signals from the niche, where stem cells are found, which is able to promote quiescent state and cell cycle activation in somatic stem cells. Asymmetric division is characteristic of somatic stem cells, maintaining the reservoir of stem cells in the tissue and production of specialized cells of the same.
Stem cells show an elevated therapeutic potential, mainly in hemato-oncologic pathologies, such as leukemia and lymphomas. Little groups of stem cells were found into tumours, calling cancer stem cells. There are evidences that these cells promote tumor growth and metastasis.
Oocytes
The
oocyte
An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ...
is the female cell involved in reproduction. There is a close relationship between the oocyte and the surrounding
follicular cells which is crucial to the development of both.
GDF9
Growth/differentiation factor 9 is a protein that in humans is encoded by the ''GDF9'' gene.
Growth factors synthesized by ovarian somatic cells directly affect oocyte growth and function. Growth differentiation factor-9 (GDF9) is expressed in o ...
and
BMP15
Bone morphogenetic protein 15 (BMP-15) is a protein that in humans is encoded by the BMP15 gene. It is involved in folliculogenesis, the process in which primordial follicles develop into pre-ovulatory follicles.
Structure & Interactions
Stru ...
produced by the oocyte bind to
BMPR2
Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase. It binds Bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signalling. BMPs are involved in a ho ...
receptors on follicular cells activating
SMADs 2/3, ensuring follicular development. Concomitantly, oocyte growth is initiated by binding of
KITL to its receptor KIT in the oocyte, leading to the activation of
PI3K/Akt pathway, allowing oocyte survival and development. During
embryogenesis
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
, oocytes initiate
meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
and stop in prophase I. This arrest is maintained by elevated levels of
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
within the oocyte.
It was recently suggested that
cGMP cooperates with cAMP to maintain the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
arrest.
During meiotic maturation, the
LH peak that precedes
ovulation
Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized ...
activates
MAPK pathway
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
leading to
gap junction
Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regulate ...
disruption and breakdown of communication between the oocyte and the follicular cells.
PDE3A is activated and degrades cAMP, leading to cell cycle progression and oocyte maturation. The LH surge also leads to the production of
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
and
prostaglandins
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
that induce the expression of
ADAMTS1 and other proteases, as well as their inhibitors. This will lead to degradation of the follicular wall, but limiting the damage and ensuring that the rupture occurs in the appropriate location, releasing the oocyte into the
Fallopian tubes
The fallopian tubes, also known as uterine tubes, oviducts or salpinges (singular salpinx), are paired tubes in the human female that stretch from the uterus to the ovaries. The fallopian tubes are part of the female reproductive system. In ot ...
.
Oocyte activation depends on fertilization by sperm. It is initiated with sperm's attraction induced by prostaglandins produced by the oocyte, which will create a gradient that will influence the sperm's direction and velocity. After fusion with the oocyte,
PLC ζ of the spermatozoa is released into the oocyte leading to an increase in Ca2+ levels that will activate
CaMKII
/calmodulin-dependent protein kinase II (CaM kinase II or CaMKII) is a serine/threonine-specific protein kinase that is regulated by the / calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediato ...
which will degrade
MPF, leading to the resumption of meiosis. The increased Ca
2+ levels will induce the
exocytosis
Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use o ...
of
cortical granules
Cortex or cortical may refer to:
Biology
* Cortex (anatomy), the outermost layer of an organ
** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain''
*** Motor cortex, the regions of the cerebral cortex i ...
that degrade
ZP receptors, used by sperm to penetrate the oocyte, blocking
polyspermy
In biology, polyspermy describes the fertilization of an egg by more than one sperm. Diploid organisms normally contain two copies of each chromosome, one from each parent. The cell resulting from polyspermy, on the other hand, contains three or ...
. Deregulation of these pathways will lead to several diseases like, oocyte maturation failure syndrome which results in
infertility
Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...
. Increasing our molecular knowledge of oocyte development mechanisms could improve the outcome of
assisted reproduction procedures, facilitating conception.
Spermatozoon
Spermatozoon
A spermatozoon (; also spelled spermatozoön; ; ) is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote. (A zygote is a single cell, with a complete set of chromosomes, t ...
is the male gamete. After ejaculation this cell is not mature, so it can not fertilize the oocyte. To have the ability to fertilize the female gamete, this cell suffers
capacitation
Capacitation is the penultimate step in the maturation of mammalian spermatozoa and is required to render them competent to fertilize an oocyte. This step is a biochemical event; the sperm move normally and look mature prior to capacitation.
''I ...
and
acrosome reaction
During fertilization, a sperm must first fuse with the plasma membrane and then penetrate the female egg cell to fertilize it. Fusing to the egg cell usually causes little problem, whereas penetrating through the egg's hard shell or extracellular ...
in female reproductive tract. The signaling pathways best described for spermatozoon involve these processes. The
cAMP/PKA signaling pathway leads to sperm cells capacitation; however,
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
in sperm cells is different from the somatic cells. Adenylyl cyclase in spermatozoon does not recognize
G proteins
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
, so it is stimulated by bicarbonate and Ca
2+ ions. Then, it converts
adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
into cyclic AMP, which activates
Protein kinase A
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
. PKA leads to protein tyrosine phosphorylation.
Phospholipase C
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
(PLC) is involved in acrosome reaction.
ZP3
Zona pellucida sperm-binding protein 3, also known as zona pellucida glycoprotein 3 (Zp-3) or the sperm receptor, is a ZP module-containing protein that in humans is encoded by the ''ZP3'' gene. ZP3 is the receptor in the zona pellucida which bin ...
is a glycoprotein present in
zona pelucida and it interacts with receptors in spermatozoon. So, ZP3 can activate
G protein coupled receptors
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
and
tyrosine kinase receptors
Receptor tyrosine kinases (RTKs) are the high-dissociation constant#Protein-ligand binding, affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the hu ...
, that leads to production of PLC. PLC cleaves the phospholipid
phosphatidylinositol 4,5-bisphosphate
Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
(PIP2) into
diacyl glycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as sur ...
(DAG) and
inositol 1,4,5-trisphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the ...
. IP3 is released as a soluble structure into the cytosol and DAG remains bound to the membrane. IP3 binds to IP3 receptors, present in acrosome membrane. In addition, calcium and DAG together work to activate
protein kinase C
In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
, which goes on to phosphorylate other molecules, leading to altered cellular activity. These actions cause an increase in cytosolic concentration of Ca
2+ that leads to dispersion of
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
and consequently promotes plasmatic membrane and outer acrosome membrane fusion.
Progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
is a steroid hormone produced in cumulus oophorus. In
somatic cells
A somatic cell (from Ancient Greek σῶμα ''sôma'', meaning "body"), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Such cells compo ...
it binds to receptors in
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
; however, in spermatozoon its receptors are present in plasmatic membrane. This hormone activates AKT that leads to activation of other protein kinases, involved in capacitation and acrosome reaction.
When
ROS (reactive oxygen species) are present in high concentration, they can affect the physiology of cells, but when they are present in moderated concentration they are important for acrosome reaction and capacitation. ROS can interact with cAMP/PKA and progesterone pathway, stimulating them. ROS also interacts with
ERK pathway
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
The signal starts when a signaling m ...
that leads to activation of Ras, MEK and MEK-like proteins. These proteins activate
protein tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
(PTK) that phosphorylates various proteins important for capacitation and acrosome reaction.
Embryos
Various signalling pathways, as FGF,
WNT and
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
pathways, regulate the processes involved in
embryogenesis
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
.
FGF (Fibroblast Growth Factor) ligands bind to
receptors tyrosine kinase,
FGFR (Fibroblast Growth Factor Receptors), and form a stable complex with co-receptors HSPG (Heparan Sulphate Proteoglycans) that will promote
autophosphorylation
Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or ...
of the intracellular domain of FGFR and consequent activation of four main pathways:
MAPK/ERK
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
The signal starts when a signaling ...
,
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
, PLCγ and
JAK/STAT.
*
MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
/
ERK (Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase) regulates gene
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
through successive kinase
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
and in human embryonic stem cells it helps maintaining pluripotency.
However, in the presence of Activin A, a TGF-β ligand, it causes the formation of
mesoderm
The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical E ...
and
neuroectoderm
Neuroectoderm (or neural ectoderm or neural tube epithelium) consists of cells derived from ectoderm. Formation of the neuroectoderm is first step in the development of the nervous system. The neuroectoderm receives bone morphogenetic protein-inh ...
.
* Phosphorylation of membrane phospholipids by
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
(Phosphatidylinositol 3-Kinase) results in activation of
AKT/PKB (Protein Kinase B). This kinase is involved in cell survival and inhibition of
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, cellular growth and maintenance of
pluripotency Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta.
According to Latin terms, Pluripotentia means the ability for many thin ...
, in
embryonic stem cells
Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they co ...
.
*
PLCγ (Phosphoinositide Phospholipase C γ) hydrolyzes membrane phospholipids to form IP3 (Inositoltriphosphate) and
DAG (Diacylglycerol), leading to activation of kinases and regulating morphogenic movements during
gastrulation
Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. Be ...
and
neurulation
Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neurula.
The process begins when the notochord induces the formati ...
.
*
STAT
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
(Signal Trandsducer and Activator of Transcription) is phosphorylated by JAK (Janus Kinase) and regulates gene transcription, determining cell fates. In mouse embryonic stem cells, this pathway helps maintaining pluripotency.
The WNT pathway allows
β-catenin
Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcriptio ...
function in gene transcription, once the interaction between WNT ligand and
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
Frizzled
Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.
Species distribution
Fri ...
inhibits
GSK-3
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen ...
(Glycogen Synthase Kinase-3) and thus formation of β-catenin destruction complex.
Although there is some controversy about the effects of this pathway in embryogenesis, it is thought that WNT signalling induces
primitive streak
The primitive streak is a structure that forms in the early embryo in amniotes. In amphibians the equivalent structure is the blastopore. During early embryonic development, the embryonic disc becomes oval shaped, and then pear-shaped with the ...
, mesoderm and
endoderm
Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...
formation.
In
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
(Transforming Growth Factor β) pathway,
BMP (Bone Morphogenic Protein),
Activin
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual ...
and
Nodal
Nodal homolog is a secretory protein that in humans is encoded by the ''NODAL'' gene which is located on chromosome 10q22.1. It belongs to the transforming growth factor beta superfamily (TGF-β superfamily). Like many other members of this superf ...
ligands bind to their receptors and activate
Smads that bind to
DNA and promote gene transcription.
Activin is necessary for mesoderm and specially endoderm
differentiation, and Nodal and BMP are involved in embryo patterning. BMP is also responsible for formation of extra-embryonic tissues before and during gastrulation, and for early mesoderm differentiation, when Activin and FGF pathways are activated.
Pathway construction
Pathway building has been performed by individual groups studying a network of interest (e.g., immune signaling pathway) as well as by large bioinformatics consortia (e.g., the Reactome Project) and commercial entities (e.g.,
Ingenuity Systems
QIAGEN Silicon Valley (formerly known as Ingenuity Systems, Inc) is a company based in Redwood City, California, USA, to analyze complex biological systems. QIAGEN Silicon Valley's first product, IPA, was introduced in 2003, and is used to help r ...
). Pathway building is the process of identifying and integrating the entities, interactions, and associated annotations, and populating the knowledge base. Pathway construction can have either a data-driven objective (DDO) or a knowledge-driven objective (KDO). Data-driven pathway construction is used to generate relationship information of genes or proteins identified in a specific experiment such as a microarray study.
Knowledge-driven pathway construction entails development of a detailed pathway knowledge base for particular domains of interest, such as a cell type, disease, or system. The curation process of a biological pathway entails identifying and structuring content, mining information manually and/or computationally, and assembling a knowledgebase using appropriate software tools. A schematic illustrating the major steps involved in the data-driven and knowledge-driven construction processes.
For either DDO or KDO pathway construction, the first step is to mine pertinent information from relevant information sources about the entities and interactions. The information retrieved is assembled using appropriate formats, information standards, and pathway building tools to obtain a pathway prototype. The pathway is further refined to include context-specific annotations such as species, cell/tissue type, or disease type. The pathway can then be verified by the domain experts and updated by the curators based on appropriate feedback. Recent attempts to improve knowledge integration have led to refined classifications of cellular entities, such as GO, and to the assembly of structured knowledge repositories. Data repositories, which contain information regarding sequence data, metabolism, signaling, reactions, and interactions are a major source of information for pathway building. A few useful databases are described in the following table.
Legend: Y – Yes, N – No; BIND – Biomolecular Interaction Network Database, DIP – Database of Interacting Proteins, GNPV – Genome Network Platform Viewer, HPRD = Human Protein Reference Database, MINT – Molecular Interaction database, MIPS – Munich Information center for Protein Sequences, UNIHI – Unified Human Interactome, OPHID – Online Predicted Human Interaction Database, EcoCyc – Encyclopaedia of E. Coli Genes and Metabolism, MetaCyc – aMetabolic Pathway database, KEGG – Kyoto Encyclopedia of Genes and Genomes, PANTHER – Protein Analysis Through Evolutionary Relationship database, STKE – Signal Transduction Knowledge Environment, PID – The Pathway Interaction Database, BioPP – Biological Pathway Publisher. A comprehensive list of resources can be found at http://www.pathguide.org.
Pathway-related databases and tools
KEGG
The increasing amount of genomic and molecular information is the basis for understanding higher-order biological systems, such as the cell and the organism, and their interactions with the environment, as well as for medical, industrial and other practical applications. The
KEGG
KEGG (Kyoto Encyclopedia of Genes and Genomes) is a collection of databases dealing with genomes, biological pathways, diseases, drugs, and chemical substances. KEGG is utilized for bioinformatics research and education, including data analysis i ...
resource provides a reference knowledge base for linking genomes to biological systems, categorized as building blocks in the genomic space (KEGG GENES), the chemical space (KEGG LIGAND), wiring diagrams of interaction networks and reaction networks (KEGG PATHWAY), and ontologies for pathway reconstruction (BRITE database).
The KEGG PATHWAY database is a collection of manually drawn pathway maps for
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
, genetic information processing, environmental information processing such as signal transduction,
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
–receptor interaction and cell communication, various other cellular processes and human diseases, all based on extensive survey of published literature.
GenMAPP
Gene Map Annotator and Pathway Profiler (
GenMAPP
GenMAPP (Gene Map Annotator and Pathway Profiler) is a free, open-source bioinformatics software tool designed to visualize and analyze genomic data in the context of pathways (metabolic, signaling), connecting gene-level datasets to biological p ...
) a free, open-source, stand-alone computer program is designed for organizing, analyzing, and sharing genome scale data in the context of biological pathways.
GenMAPP
GenMAPP (Gene Map Annotator and Pathway Profiler) is a free, open-source bioinformatics software tool designed to visualize and analyze genomic data in the context of pathways (metabolic, signaling), connecting gene-level datasets to biological p ...
database support multiple gene annotations and species as well as custom species database creation for a potentially unlimited number of species. Pathway resources are expanded by utilizing homology information to translate pathway content between species and extending existing pathways with data derived from conserved protein interactions and coexpression. A new mode of data visualization including time-course,
single nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
(SNP), and
splicing, has been implemented with
GenMAPP
GenMAPP (Gene Map Annotator and Pathway Profiler) is a free, open-source bioinformatics software tool designed to visualize and analyze genomic data in the context of pathways (metabolic, signaling), connecting gene-level datasets to biological p ...
database to support analysis of complex data.
GenMAPP
GenMAPP (Gene Map Annotator and Pathway Profiler) is a free, open-source bioinformatics software tool designed to visualize and analyze genomic data in the context of pathways (metabolic, signaling), connecting gene-level datasets to biological p ...
also offers innovative ways to display and share data by incorporating
HTML
The HyperText Markup Language or HTML is the standard markup language for documents designed to be displayed in a web browser. It can be assisted by technologies such as Cascading Style Sheets (CSS) and scripting languages such as JavaScri ...
export of analyses for entire sets of pathways as organized web pages. In short,
GenMAPP
GenMAPP (Gene Map Annotator and Pathway Profiler) is a free, open-source bioinformatics software tool designed to visualize and analyze genomic data in the context of pathways (metabolic, signaling), connecting gene-level datasets to biological p ...
provides a means to rapidly interrogate complex experimental data for pathway-level changes in a diverse range of organisms.
Reactome
Given the genetic makeup of an organism, the complete set of possible reactions constitutes its
reactome
Reactome is a free online database of biological pathways. There are several Reactomes that concentrate on specific organisms, the largest of these is focused on human biology, the following description concentrates on the human Reactome. It is au ...
.
Reactome
Reactome is a free online database of biological pathways. There are several Reactomes that concentrate on specific organisms, the largest of these is focused on human biology, the following description concentrates on the human Reactome. It is au ...
, located at http://www.reactome.org is a curated, peer-reviewed resource of human biological processes/pathway data. The basic unit of the Reactome database is a reaction; reactions are then grouped into causal chains to form pathways The Reactome data model allows us to represent many diverse processes in the human system, including the pathways of intermediary metabolism, regulatory pathways, and signal transduction, and high-level processes, such as the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
. Reactome provides a qualitative framework, on which quantitative data can be superimposed. Tools have been developed to facilitate custom data entry and annotation by expert biologists, and to allow visualization and exploration of the finished dataset as an interactive process map. Although the primary curational domain is pathways from Homo sapiens, electronic projections of human pathways onto other organisms are regularly created via putative orthologs, thus making Reactome relevant to model organism research communities. The database is publicly available under open source terms, which allows both its content and its software infrastructure to be freely used and redistributed. Studying whole transcriptional profiles and cataloging protein–protein interactions has yielded much valuable biological information, from the genome or proteome to the physiology of an organism, an organ, a tissue or even a single cell. The Reactome database containing a framework of possible reactions which, when combined with expression and enzyme kinetic data, provides the infrastructure for quantitative models, therefore, an integrated view of biological processes, which links such gene products and can be systematically mined by using bioinformatics applications. Reactome data available in a variety of standard formats, including
BioPAX BioPAX (Biological Pathway Exchange) is a RDF/OWL-based
standard language to represent biological pathways
at the molecular and cellular level. Its major use is to facilitate the exchange of pathway data.
Pathway data captures our understanding of ...
,
SBML
The Systems Biology Markup Language (SBML) is a representation format, based on XML, for communicating and storing computational models of biological processes. It is a free and open standard with widespread software support and a community of use ...
and PSI-MI, and also enable data exchange with other pathway databases, such as the Cycs,
KEGG
KEGG (Kyoto Encyclopedia of Genes and Genomes) is a collection of databases dealing with genomes, biological pathways, diseases, drugs, and chemical substances. KEGG is utilized for bioinformatics research and education, including data analysis i ...
and
amaze Amaze may refer to:
* Amaze (software), a digital accessibility technology
* Amaze Entertainment, a video game development company
* Honda Amaze
The Honda Amaze (also known as Honda Brio Amaze for the first generation) is a 4-door subcompact se ...
, and molecular interaction databases, such as
BIND
BIND () is a suite of software for interacting with the Domain Name System (DNS). Its most prominent component, named (pronounced ''name-dee'': , short for ''name daemon''), performs both of the main DNS server roles, acting as an authoritative n ...
and
HPRD
The Human Protein Reference Database (HPRD) is a protein database accessible through the Internet. It is closely associated with the premier Indian Non-Profit research organisation Institute of Bioinformatics (IOB), Bangalore. This database is a c ...
. The next data release will cover apoptosis, including the death receptor signaling pathways, and the Bcl2 pathways, as well as pathways involved in
hemostasis
In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, whi ...
. Other topics currently under development include several signaling pathways,
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
, visual
phototransduction Visual phototransduction is the transduction (physiology), sensory transduction process of the visual system by which light is detected to yield Action potential, nerve impulses in the rod cells and cone cells in the retina of the eye in humans and ...
and
hematopoeisis. In summary, Reactome provides high-quality curated summaries of fundamental biological processes in humans in a form of biologist-friendly visualization of pathways data, and is an open-source project.
Pathway-oriented approaches
In the post-genomic age, high-throughput
sequencing
In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which succ ...
and gene/protein profiling techniques have transformed biological research by enabling comprehensive monitoring of a biological system, yielding a list of differentially expressed genes or proteins, which is useful in identifying genes that may have roles in a given phenomenon or phenotype. With
DNA microarrays
A DNA microarray (also commonly known as DNA chip or biochip) is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to ...
and genome-wide gene engineering, it is possible to screen global gene expression profiles to contribute a wealth of
genomic
Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...
data to the public domain. With RNA interference, it is possible to distill the inferences contained in the experimental literature and primary databases into knowledge bases that consist of annotated representations of biological pathways. In this case, individual genes and proteins are known to be involved in biological processes, components, or structures, as well as how and where gene products interact with each other. Pathway-oriented approaches for analyzing microarray data, by grouping long lists of individual genes, proteins, and/or other biological molecules according to the pathways they are involved in into smaller sets of related genes or proteins, which reduces the complexity, have proven useful for connecting genomic data to specific biological processes and systems. Identifying active pathways that differ between two conditions can have more explanatory power than a simple list of different genes or proteins. In addition, a large number of pathway analytic methods exploit pathway knowledge in public repositories such as
Gene Ontology
The Gene Ontology (GO) is a major bioinformatics initiative to unify the representation of gene and gene product attributes across all species. More specifically, the project aims to: 1) maintain and develop its controlled vocabulary of gene and g ...
(GO) or Kyoto Encyclopedia of Genes and Genomes (
KEGG
KEGG (Kyoto Encyclopedia of Genes and Genomes) is a collection of databases dealing with genomes, biological pathways, diseases, drugs, and chemical substances. KEGG is utilized for bioinformatics research and education, including data analysis i ...
), rather than inferring pathways from molecular measurements. Furthermore, different research focuses have given the word "pathway" different meanings. For example, 'pathway' can denote a metabolic pathway involving a sequence of enzyme-catalyzed reactions of small molecules, or a signaling pathway involving a set of protein phosphorylation reactions and gene regulation events. Therefore, the term "pathway analysis" has a very broad application. For instance, it can refer to the analysis physical interaction networks (e.g., protein–protein interactions), kinetic simulation of pathways, and steady-state pathway analysis (e.g., flux-balance analysis), as well as its usage in the inference of pathways from expression and sequence data. Several functional enrichment analysis tools and algorithms have been developed to enhance data interpretation. The existing knowledge base–driven pathway analysis methods in each generation have been summarized in recent literature.
Applications of pathway analysis in medicine
Colorectal cancer (CRC)
A program package MatchMiner was used to scan
HUGO
Hugo or HUGO may refer to:
Arts and entertainment
* ''Hugo'' (film), a 2011 film directed by Martin Scorsese
* Hugo Award, a science fiction and fantasy award named after Hugo Gernsback
* Hugo (franchise), a children's media franchise based on ...
names for cloned genes of interest are scanned, then are input into GoMiner, which leveraged the GO to identify the biological processes, functions and components represented in the gene profile. Also, Database for Annotation, Visualization, and Integrated Discovery (
DAVID
David (; , "beloved one") (traditional spelling), , ''Dāwūd''; grc-koi, Δαυΐδ, Dauíd; la, Davidus, David; gez , ዳዊት, ''Dawit''; xcl, Դաւիթ, ''Dawitʿ''; cu, Давíдъ, ''Davidŭ''; possibly meaning "beloved one". w ...
) and
KEGG
KEGG (Kyoto Encyclopedia of Genes and Genomes) is a collection of databases dealing with genomes, biological pathways, diseases, drugs, and chemical substances. KEGG is utilized for bioinformatics research and education, including data analysis i ...
database can be used for the analysis of microarray expression data and the analysis of each GO biological process (P), cellular component (C), and molecular function (F) ontology. In addition,
DAVID
David (; , "beloved one") (traditional spelling), , ''Dāwūd''; grc-koi, Δαυΐδ, Dauíd; la, Davidus, David; gez , ዳዊት, ''Dawit''; xcl, Դաւիթ, ''Dawitʿ''; cu, Давíдъ, ''Davidŭ''; possibly meaning "beloved one". w ...
tools can be used to analyze the roles of genes in metabolic pathways and show the biological relationships between genes or gene-products and may represent metabolic pathways. These two databases also provide bioinformatics tools online to combine specific biochemical information on a certain organism and facilitate the interpretation of biological meanings for experimental data. By using a combined approach of Microarray-Bioinformatic technologies, a potential metabolic mechanism contributing to
colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
(CRC) has been demonstrated
Several environmental factors may be involved in a series of points along the genetic pathway to CRC. These include genes associated with bile acid metabolism,
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
metabolism and fatty acid metabolism pathways, supporting a hypothesis that some metabolic alternations observed in colon carcinoma may occur in the development of CRC.
Parkinson's disease (PD)
Cellular models are instrumental in dissecting a complex pathological process into simpler molecular events. Parkinson's disease (PD) is multifactorial and clinically heterogeneous; the aetiology of the sporadic (and most common) form is still unclear and only a few molecular mechanisms have been clarified so far in the neurodegenerative cascade. In such a multifaceted picture, it is particularly important to identify experimental models that simplify the study of the different networks of proteins and genes involved. Cellular models that reproduce some of the features of the neurons that degenerate in PD have contributed to many advances in our comprehension of the pathogenic flow of the disease. In particular, the pivotal biochemical pathways (i.e.
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
and oxidative stress, mitochondrial impairment and dysfunctional mitophagy, unfolded protein stress and improper removal of misfolded proteins) have been widely explored in cell lines, challenged with toxic insults or genetically modified. The central role of a-synuclein has generated many models aiming to elucidate its contribution to the dysregulation of various cellular processes. Classical cellular models appear to be the correct choice for preliminary studies on the molecular action of new drugs or potential toxins and for understanding the role of single genetic factors. Moreover, the availability of novel cellular systems, such as cybrids or induced pluripotent stem cells, offers the chance to exploit the advantages of an in vitro investigation, although mirroring more closely the cell population being affected.
Alzheimer's disease (AD)
Synapse, Synaptic degeneration and death of nerve cells are defining features of Alzheimer's disease (AD), the most prevalent age-related neurodegenerative disorders. In AD, neurons in the hippocampus and basal forebrain (brain regions that subserve learning and memory functions) are selectively vulnerable. Studies of postmortem brain tissue from AD people have provided evidence for increased levels of oxidative stress, mitochondrial dysfunction and impaired glucose uptake in vulnerable neuronal populations. Studies of animal and cell culture models of AD suggest that increased levels of oxidative stress (membrane lipid peroxidation, in particular) may disrupt neuronal energy metabolism and ion homeostasis, by impairing the function of membrane ion-motive ATPases, glucose and glutamate transporters. Such oxidative and metabolic compromise may thereby render neurons vulnerable to excitotoxicity and
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. Recent studies suggest that AD can manifest systemic alterations in energy metabolism (e.g., increased insulin resistance and dysregulation of glucose metabolism). Emerging evidence that dietary restriction can forestall the development of AD is consistent with a major "metabolic" component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable.
References
External links
KEGG resourceDAVID toolsGenMAPPGoMinerPathguide
{{DEFAULTSORT:Biochemical Cascade
Biological processes
Chemical kinetics
Enzyme kinetics
Chemical processes
Complement system
Signal transduction