A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of
protein kinase
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
that is specific to the
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
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 ...
and
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
(i.e., a
serine/threonine-specific protein kinase
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 ...
). MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as
mitogen
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
s,
osmotic stress
Osmotic shock or osmotic stress is physiologic dysfunction caused by a sudden change in the solute concentration around a cell, which causes a rapid change in the movement of water across its cell membrane. Under hypertonic conditions - conditions ...
,
heat shock
The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal ...
and
proinflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include inte ...
s. They regulate cell functions including
proliferation,
gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
,
differentiation,
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 ...
, cell survival, 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 ...
.
MAP kinases are found in
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s only, but they are fairly diverse and encountered in all animals, fungi and plants, and even in an array of unicellular eukaryotes.
MAPKs belong to the CMGC (CDK/MAPK/GSK3/CLK) kinase group. The closest relatives of MAPKs are the
cyclin-dependent kinase
Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They a ...
s (CDKs).
Discovery
The first mitogen-activated protein kinase to be discovered was ERK1 (
MAPK3
Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene.
Function
The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) famil ...
) in mammals. Since ERK1 and its close relative ERK2 (
MAPK1
Mitogen-activated protein kinase 1, (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the ''MAPK1'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracel ...
) are both involved in growth factor signaling, the family was termed "mitogen-activated". With the discovery of other members, even from distant organisms (e.g. plants), it has become increasingly clear that the name is a misnomer, since most MAPKs are actually involved in the response to potentially harmful, abiotic stress stimuli (hyperosmosis, oxidative stress, DNA damage, low osmolarity, infection, etc.). Because plants cannot "flee" from stress, terrestrial plants have the highest number of MAPK genes per organism ever found. Thus the role of mammalian ERK1/2 kinases as regulators of cell proliferation is not a generic, but a highly specialized function.
Types
Most MAPKs have a number of shared characteristics, such as the activation dependent on two
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 ...
events, a three-tiered pathway architecture and similar substrate recognition sites. These are the "classical" MAP kinases. But there are also some ancient outliers from the group as sketched above, that do not have dual phosphorylation sites, only form two-tiered pathways, and lack the features required by other MAPKs for substrate binding. These are usually referred to as "atypical" MAPKs.
It is yet unclear if the atypical MAPKs form a single group as opposed to the classical ones.
The mammalian MAPK family of kinases includes three subfamilies:
#
Extracellular signal-regulated kinases
In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and p ...
(ERKs)
#
c-Jun N-terminal kinases
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 are res ...
(JNKs)
#
p38 mitogen-activated protein kinases
p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differe ...
(p38s)
Generally, ERKs are activated by
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
s and
mitogen
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
s, whereas
cellular stresses and
inflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include in ...
s activate JNKs and p38s.
Activation
![ERK2-phosphorylated](https://upload.wikimedia.org/wikipedia/commons/f/fd/ERK2-phosphorylated.png)
Mitogen-activated protein kinases are catalytically inactive in their base form. In order to become active, they require (potentially multiple) phosphorylation events in their activation loops. This is conducted by specialized enzymes of the STE protein kinase group. In this way
protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these stat ...
can induce a
conformational change
In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors.
A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
in the structure of the protein via long-range
allostery
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric site ...
.
In the case of classical MAP kinases, the
activation loop
In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA. IDPs rang ...
contains a characteristic TxY (threonine-x-tyrosine) motif (TEY in mammalian
ERK1
Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene.
Function
The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) famil ...
and
ERK2
Mitogen-activated protein kinase 1, (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the ''MAPK1'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extrace ...
, TDY in
ERK5
Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the ''MAPK7'' gene.
Function
MAPK7 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...
, TPY in
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 are ...
s, TGY in
p38 kinases) that needs to be phosphorylated on both the
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
and the
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
residues in order to lock the kinase domain in a catalytically competent conformation.
In vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
and
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
, phosphorylation of tyrosine oftentimes precedes phosphorylation of threonine, although phosphorylation of either residue can occur in the absence of the other.
This tandem
activation loop
In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA. IDPs rang ...
phosphorylation (that was proposed to be either distributive or processive, dependent on cellular environment) is performed by members of the Ste7 protein kinase family, also known as
MAP2 kinases. MAP2 kinases in turn, are also activated by phosphorylation, by a number of different upstream serine-threonine kinases (
MAP3 kinases). Because MAP2 kinases display very little activity on substrates other than their cognate MAPK, classical MAPK pathways form multi-tiered, but relatively linear pathways. These pathways can effectively convey stimuli from the cell membrane (where many
MAP3Ks are activated) to the nucleus (where only MAPKs may enter) or to many other subcellular targets.
In comparison to the three-tiered classical MAPK pathways, some atypical MAP kinases appear to have a more ancient, two-tiered system.
ERK3 (MAPK6) and
ERK4
Mitogen-activated protein kinase 4 is an enzyme that in humans is encoded by the ''MAPK4'' gene.
Mitogen-activated protein kinase 4 is a member of the mitogen-activated protein kinase family. Tyrosine kinase growth factor receptors activate mitoge ...
(MAPK4) were recently shown to be directly phosphorylated and thus activated by
PAK kinases (related to other MAP3 kinases).
In contrast to the classical MAP kinases, these atypical MAPKs require only a single residue in their activation loops to be phosphorylated. The details of
NLK
Serine/threonine protein kinase NLK is an enzyme that in humans is encoded by the ''NLK'' gene. Its name is an abbreviation for ''Nemo-Like Kinase'', Nemo (nmo) being the ''Drosophila'' ortholog
Sequence homology is the biological homology b ...
and
ERK7 (MAPK15) activation remain unknown.
Inactivation of MAPKs is performed by a number of
phosphatase
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
s. A very conserved family of dedicated phosphatases is the so-called
MAP kinase phosphatase
MAPK phosphatases (MKPs) are the largest class of phosphatases involved in down-regulating Mitogen-activated protein kinases (MAPK) signaling. MAPK signalling pathways regulate multiple features of development and homeostasis. This can involve gene ...
s (MKPs), a subgroup of
dual-specificity phosphatases (DUSPs).
As their name implies, these enzymes are capable of hydrolyzing the phosphate from both phosphotyrosine and the phosphothreonine residues. Since removal of either phosphate groups will greatly reduce MAPK activity, essentially abolishing signaling, some
tyrosine phosphatase
Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:
: proteintyrosine phosphate + H2O = ...
s are also involved in inactivating MAP kinases (e.g. the phosphatases
HePTP
Protein tyrosine phosphatase non-receptor type 7 is an enzyme that in humans is encoded by the ''PTPN7'' gene.
Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signali ...
,
STEP
Step(s) or STEP may refer to:
Common meanings
* Stairs#Step, Steps, making a staircase
* Walking
* Dance move
* Military step, or march
** Marching
Arts Films and television
* Steps (TV series), ''Steps'' (TV series), Hong Kong
* Step (film), ' ...
and
PTPRR
Protein tyrosine phosphatase receptor-type R is an enzyme that in humans is encoded by the ''PTPRR'' gene.
Function
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling mo ...
in mammals).
Signaling cascades
![Raf-activation-cycle-sketch](https://upload.wikimedia.org/wikipedia/commons/a/a7/Raf-activation-cycle-sketch.png)
As mentioned above, MAPKs typically form multi-tiered pathways, receiving input several levels above the actual MAP kinase. In contrast to the relatively simple, phosphorylation-dependent activation mechanism of MAPKs and
MAP2K
Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
MAP2K is classified as .
There are seven genes:
* (a.k.a. MEK1)
* (a.k ...
s, MAP3Ks have stunningly complex regulation. Many of the better-known
MAP3Ks, such as
c-Raf
RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the ''RAF1'' gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase ( ...
,
MEKK4
Mitogen Activated Protein (MAP) kinase kinase kinase, MAPKKK (or MAP3K) is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but ar ...
or
MLK3
Mitogen-activated protein kinase kinase kinase 11 is an enzyme that in humans is encoded by the ''MAP3K11'' gene.
Function
The protein encoded by this gene is called MLK3 and it is a member of the serine/threonine kinase family. This kinase co ...
require multiple steps for their activation. These are typically allosterically-controlled enzymes, tightly locked into an inactive state by multiple mechanisms. The first step en route to their activation consist of relieving their autoinhibition by a smaller ligand (such as
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 ...
for
c-Raf
RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the ''RAF1'' gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase ( ...
,
GADD45 for
MEKK4
Mitogen Activated Protein (MAP) kinase kinase kinase, MAPKKK (or MAP3K) is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but ar ...
or
Cdc42 for
MLK3
Mitogen-activated protein kinase kinase kinase 11 is an enzyme that in humans is encoded by the ''MAP3K11'' gene.
Function
The protein encoded by this gene is called MLK3 and it is a member of the serine/threonine kinase family. This kinase co ...
). This commonly (but not always) happens at the cell membrane, where most of their activators are bound (note that
small G-proteins are constitutively membrane-associated due to
prenylation
Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...
). That step is followed by side-to-side homo- and heterodimerisation of their now accessible kinase domains. Recently determined complex structures reveal that the dimers are formed in an orientation that leaves both their substrate-binding regions free.
Importantly, this dimerisation event also forces the MAP3 kinase domains to adopt a partially active conformation. Full activity is only achieved once these dimers transphosphorylate each other on their activation loops. The latter step can also be achieved or aided by auxiliary protein kinases (MAP4 kinases, members of the Ste20 family). Once a MAP3 kinase is fully active, it may phosphorylate its substrate MAP2 kinases, which in turn will phosphorylate their MAP kinase substrates.
In animals
![MAPK-pathway-mammalian](https://upload.wikimedia.org/wikipedia/commons/d/d6/MAPK-pathway-mammalian.png)
The
ERK1/2 pathway of mammals is probably the best-characterized MAPK system. The most important upstream activators of this pathway are the Raf proteins (
A-Raf,
B-Raf or
c-Raf
RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the ''RAF1'' gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase ( ...
), the key mediators of response to growth factors (
EGF,
FGF,
PDGF
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
, etc.); but other MAP3Ks such as c-Mos and
Tpl2/Cot can also play the same role. All these enzymes phosphorylate and thus activate the
MKK1 and/or
MKK2 kinases, that are highly specific activators for
ERK1
Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene.
Function
The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) famil ...
and
ERK2
Mitogen-activated protein kinase 1, (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the ''MAPK1'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extrace ...
. The latter phosphorylate a number of substrates important for
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
,
cell cycle progression
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 subse ...
,
cell division
Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
and
differentiation (
RSK kinases,
Elk-1 transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
, etc.)
In contrast to the relatively well-insulated
ERK1/2 pathway, mammalian
p38 and
JNK kinases have most of their activators shared at the MAP3K level (
MEKK1,
MEKK4
Mitogen Activated Protein (MAP) kinase kinase kinase, MAPKKK (or MAP3K) is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but ar ...
,
ASK1
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and ...
,
TAK1,
MLK3
Mitogen-activated protein kinase kinase kinase 11 is an enzyme that in humans is encoded by the ''MAP3K11'' gene.
Function
The protein encoded by this gene is called MLK3 and it is a member of the serine/threonine kinase family. This kinase co ...
,
TAOK1
Serine/threonine-protein kinase TAO1 is an enzyme that in humans is encoded by the ''TAOK1'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''gener ...
, etc.). In addition, some MAP2K enzymes may activate both p38 and JNK (
MKK4
Dual-specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the ''MAP2K4'' gene.
''MAP2K4'' encodes a dual-specificity kinase that belongs to the Ser/Thr protein kinase family. MAP2K4 phosphorylates MAP ...
), while others are more specific for either JNK (
MKK7
Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the ''MAP2K7'' gene. This protein is a member of the mitogen-activated protein kinase kinase family. T ...
) or p38 (
MKK3
Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the ''MAP2K3'' gene.
The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This k ...
and
MKK6
Dual specificity mitogen-activated protein kinase kinase 6 also known as MAP kinase kinase 6 (MAPKK 6) or MAPK/ERK kinase 6 is an enzyme that in humans is encoded by the ''MAP2K6'' gene, on chromosome 17.
Function
MAPKK 6 is a member of the d ...
). Due to these interlocks, there are very few if any stimuli that can elicit JNK activation without simultaneously activating p38 or reversed.
Both JNK and p38 signaling pathways are responsive to stress stimuli, such as
cytokine
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 ...
s,
ultraviolet irradiation
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...
,
heat shock
The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal ...
, and
osmotic shock
Osmotic shock or osmotic stress is physiologic dysfunction caused by a sudden change in the solute concentration around a cell, which causes a rapid change in the movement of water across its cell membrane. Under hypertonic conditions - conditions ...
, and are involved in
adaptation to stress,
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 ...
or
cell differentiation
Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
. JNKs have a number of dedicated substrates that only they can phosphorylate (
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 ...
,
NFAT4, etc.), while p38s also have some unique targets (e.g. the MAPKAP kinases
MK2 and
MK3 MK3 may refer to:
* ''Mortal Kombat 3'', the third game in the '' Mortal Kombat'' series
* '' Mario Kart: Super Circuit'', the third game in the ''Mario Kart'' series, released in 2001 for the Game Boy Advance
The (GBA) is a 32-bit handheld ...
), ensuring the need for both in order to respond to stressful stimuli.
ERK5
Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the ''MAPK7'' gene.
Function
MAPK7 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...
is part of a fairly well-separated pathway in mammals. Its sole specific upstream activator
MKK5
Dual specificity mitogen-activated protein kinase kinase 5 is an enzyme that in humans is encoded by the ''MAP2K5'' gene.
Function
The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase famil ...
is turned on in response to the MAP3 kinases
MEKK2 and
MEKK3. The specificity of these interactions are provided by the unique architecture of MKK5 and MEKK2/3, both containing N-terminal PB1 domains, enabling direct heterodimerisation with each other.
The PB1 domain of MKK5 also contributes to the ERK5-MKK5 interaction: it provides a special interface (in addition to the
D-motif found in MKK5) through which MKK5 can specifically recognize its substrate ERK5.
Although the molecular-level details are poorly known, MEKK2 and MEKK3 respond to certain developmental cues to direct
endothel formation and
cardiac morphogenesis. While also implicated in brain development, the embryonic lethality of ERK5 inactivation due to
cardiac abnormalities underlines its central role in mammalian
vasculogenesis
Vasculogenesis is the process of blood vessel formation, occurring by a '' de novo'' production of endothelial cells. It is sometimes paired with angiogenesis, as the first stage of the formation of the vascular network, closely followed by angio ...
.
It is notable, that
conditional knockout of ERK5 in adult animals is also lethal, due to the widespread disruption of
endothelial barriers.
Mutations in the upstream components of the ERK5 pathway (the CCM complex) are thought to underlie
cerebral cavernous malformations
Cavernous hemangioma, also called cavernous angioma, venous malformation, or cavernoma, is a type of venous
Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from th ...
in humans.
In fungi
![MAPK-pathway-yeast](https://upload.wikimedia.org/wikipedia/commons/d/de/MAPK-pathway-yeast.png)
MAPK pathways of fungi are also well studied. In yeast, the Fus3 MAPK is responsible for cell cycle arrest and
mating
In biology, mating is the pairing of either opposite-sex or hermaphroditic organisms for the purposes of sexual reproduction. ''Fertilization'' is the fusion of two gametes. ''Copulation'' is the union of the sex organs of two sexually reproduc ...
in response to pheromone stimulation. The pheromone alpha-factor is sensed by a
seven transmembrane 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 protein family, evolution ...
. The recruitment and activation of Fus3 pathway components are strictly dependent on
heterotrimeric G-protein
Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structura ...
activation. The mating MAPK pathway consist of three tiers (Ste11-Ste7-Fus3), but the MAP2 and MAP3 kinases are shared with another pathway, the Kss1 or filamentous growth pathway. While Fus3 and Kss1 are closely related ERK-type kinases, yeast cells can still activate them separately, with the help of a scaffold protein Ste5 that is selectively recruited by the G-proteins of the mating pathway. The trick is that Ste5 can associate with and "unlock" Fus3 for Ste7 as a substrate in a tertiary complex, while it does not do the same for Kss1, leaving the filamentous growth pathway to be activated only in the absence of Ste5 recruitment.
Fungi also have a pathway reminiscent of mammalian JNK/p38 signaling. This is the Hog1 pathway: activated by high osmolarity (in ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'') or a number of other abiotic stresses (in ''
Schizosaccharomyces pombe
''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically meas ...
''). The MAP2 kinase of this pathway is called Pbs2 (related to mammalian MKK3/4/6/7), the dedicated MAP3 kinases involved in activation are Ssk2 and SSk22. The system in ''S. cerevisiae'' is activated by a sophisticated osmosensing module consisting of the Sho1 and Sln1 proteins, but it is yet unclear how other stimuli can elicit activation of Hog1. Yeast also displays a number of other MAPK pathways without close homologs in animals, such as the cell wall integrity pathway (Mpk1/Slt2) or the
sporulation
In biology, a spore is a unit of sexual or asexual reproduction that may be adapted for dispersal and for survival, often for extended periods of time, in unfavourable conditions. Spores form part of the life cycles of many plants, algae, f ...
pathway (Smk1).
In plants
Despite the high number of MAPK genes, MAPK pathways of higher plants were studied less than animal or fungal ones. Although their signaling appears very complex, the MPK3, MPK4 and MPK6 kinases of ''
Arabidopsis thaliana
''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. ''A. thaliana'' is considered a weed; it is found along the shoulders of roads and in disturbed land.
A winter a ...
'' are key mediators of responses to
osmotic shock
Osmotic shock or osmotic stress is physiologic dysfunction caused by a sudden change in the solute concentration around a cell, which causes a rapid change in the movement of water across its cell membrane. Under hypertonic conditions - conditions ...
,
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
, response to cold and involved in anti-pathogen responses.
Asai ''et al.'' 2002's model of MAPK mediated immunity passes the
effector
Effector may refer to:
*Effector (biology), a molecule that binds to a protein and thereby alters the activity of that protein
* ''Effector'' (album), a music album by the Experimental Techno group Download
* ''EFFector'', a publication of the El ...
recognition signal from
FLS2
''FLS'' genes have been discovered to be involved in flagellin reception of bacteria. FLS1 was the original gene discovered shown to correspond with a specific ecotype within ''Arabidopsis thaliana''. Even so, further studies have shown a second FL ...
⇨
MEKK1 ⇨
MKK4
Dual-specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the ''MAP2K4'' gene.
''MAP2K4'' encodes a dual-specificity kinase that belongs to the Ser/Thr protein kinase family. MAP2K4 phosphorylates MAP ...
or
MKK5
Dual specificity mitogen-activated protein kinase kinase 5 is an enzyme that in humans is encoded by the ''MAP2K5'' gene.
Function
The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase famil ...
⇨
MPK3 and
MPK6 ⇨
WRKY22 or
WRKY29 WRKY may refer to:
* WRKY (AM), a radio station (1490 AM) licensed to serve Lancaster, Pennsylvania
* WRKY-FM, a radio station (104.9 FM) licensed to Hollidaysburg, Pennsylvania
* WRKY transcription factor, proteins that bind DNA
* WRKY protein dom ...
.
However the work of Mészáros ''et al.'' 2006 and Suarez-Rodriguez ''et al.'' 2007 give other orders for this pathway and it is possible that these are parallel pathways operating simultaneously.
In addition, they are also involved in
morphogenesis
Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of devel ...
, since MPK4 mutants display severe
dwarfism
Dwarfism is a condition wherein an organism is exceptionally small, and mostly occurs in the animal kingdom. In humans, it is sometimes defined as an adult height of less than , regardless of sex; the average adult height among people with dw ...
.
Evolutionary relationships
![MAPK-evolutionary-tree](https://upload.wikimedia.org/wikipedia/commons/4/4a/MAPK-evolutionary-tree.png)
Members of the MAPK family can be found in every eukaryotic organism examined so far. In particular, both classical and atypical MAP kinases can be traced back to the root of the radiation of major eukaryotic groups. Terrestrial plants contain four groups of classical MAPKs (MAPK-A, MAPK-B, MAPK-C and MAPK-D) that are involved in response to myriads of abiotic stresses.
However, none of these groups can be directly equated to the clusters of classical MAPKs found in
opisthokont
The opisthokonts () are a broad group of eukaryotes, including both the animal and fungus kingdoms. The opisthokonts, previously called the "Fungi/Metazoa group", are generally recognized as a clade. Opisthokonts together with Apusomonadida and ...
s (fungi and animals). In the latter, the major subgroups of classical MAPKs form the ERK/Fus3-like branch (that is further sub-divided in
metazoan
Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motility, able to move, ca ...
s into ERK1/2 and ERK5 subgroups), and the p38/Hog1-like kinases (that has also split into the p38 and the JNK subgroups in multicellular animals).
In addition, there are several MAPKs in both fungi and animals, whose origins are less clear, either due to high divergence (e.g. NLK), or due to possibly being an early offshoot to the entire MAPK family (ERK3, ERK4, ERK7). In vertebrates, due to the twin whole genome duplications after the cephalochordate/vertebrate split,
there are several paralogs in every group. Thus ERK1 and ERK2 both correspond to the ''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
'' kinase ''rolled'', JNK1, JNK2 and JNK3 are all orthologous to the gene ''basket'' in ''Drosophila''. Although among the p38 group, p38 alpha and beta are clearly paralogous pairs, and so are p38 gamma and delta in vertebrates, the timing of the base split is less clear, given that many metazoans already possess multiple p38 homologs (there are three p38-type kinases in ''Drosophila'', ''Mpk2''(''p38a''), ''p38b'' and ''p38c''). The single ERK5 protein appears to fill a very specialized role (essential for vascular development in vertebrates) wherever it is present. This lineage has been deleted in
protostome
Protostomia () is the clade of animals once thought to be characterized by the formation of the organism's mouth before its anus during embryonic development. This nature has since been discovered to be extremely variable among Protostomia's memb ...
s, together with its upstream pathway components (MEKK2/3, MKK5), although they are clearly present in
cnidaria
Cnidaria () is a phylum under kingdom Animalia containing over 11,000 species of aquatic animals found both in freshwater and marine environments, predominantly the latter.
Their distinguishing feature is cnidocytes, specialized cells that th ...
ns,
sponge
Sponges, the members of the phylum Porifera (; meaning 'pore bearer'), are a basal animal clade as a sister of the diploblasts. They are multicellular organisms that have bodies full of pores and channels allowing water to circulate through t ...
s and even in certain unicellular organisms (e.g. the
choanoflagellate
The choanoflagellates are a group of free-living unicellular and colonial flagellate eukaryotes considered to be the closest living relatives of the animals. Choanoflagellates are collared flagellates, having a funnel shaped collar of interconne ...
''Monosiga brevicollis'') closely related to the origins of multicellular animals.
The split between classical and some atypical MAP kinases happened quite early. This is suggested not just by the high divergence between extant genes, but also recent discoveries of atypical MAPKs in primitive, basal eukaryotes. The genome sequencing of ''
Giardia lamblia
''Giardia duodenalis'', also known as ''Giardia intestinalis'' and ''Giardia lamblia'', is a flagellated parasitic microorganism of the genus '' Giardia'' that colonizes the small intestine, causing a diarrheal condition known as giardiasis. Th ...
'' revealed the presence of two MAPK genes, one of them similar to the already-well-known mammalian MAPKs (ERKs, p38s, etc.), the other one showing similarities to the mammalian ERK7 protein.
The situation is similar in the multicellular amoeba ''
Dictyostelium discoideum
''Dictyostelium discoideum'' is a species of soil-dwelling amoeba belonging to the phylum Amoebozoa, infraphylum Mycetozoa. Commonly referred to as slime mold, ''D. discoideum'' is a eukaryote that transitions from a collection of unicellular ...
'', where the ddERK1 protein appears to be a classical MAPK, while ddERK2 more closely resembles our ERK7 and ERK3/4 proteins.
Atypical MAPKs can also be found in higher plants, although they are poorly known. Similar to the situation in mammals, most aspects of atypical MAPKs are uncharacterized due to the lack of research focus on this area.
Substrate and partner recognition
![D-motif-overview](https://upload.wikimedia.org/wikipedia/commons/b/b8/D-motif-overview.png)
As typical for the CMGC kinase group, the catalytic site of MAP kinases has a very loose consensus sequence for
substrates. Like all their relatives, they only require the target
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 ...
/
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
amino acids to be followed by a small amino acid, preferably
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
("proline-directed kinases"). But as SP/TP sites are extremely common in all proteins, additional substrate-recognition mechanisms have evolved to ensure signaling fidelity.
Unlike their closest relatives, the
cyclin-dependent kinases
Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They a ...
(CDKs), where substrates are recognized by the
cyclin
Cyclin is a family of proteins that controls the progression of a cell through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes or group of enzymes required for synthesis of cell cycle.
Etymology
Cyclins were originally disco ...
subunit, MAPKs associate with their substrates via auxiliary binding regions on their kinase domains. The most important such region consists of the hydrophobic docking groove and the negatively charged CD-region. Together they recognize the so-called MAPK docking or D-motifs (also called kinase interaction motif / KIM). D-motifs essentially consist of one or two positively charged amino acids, followed by alternating hydrophobic residues (mostly leucines), typically upstream of the phosphorylation site by 10–50 amino acids.
Many of the known MAPK substrates contain such D-motifs that can not only bind to, but also provide specific recognition by certain MAPKs. D-motifs are not restricted to substrates: MAP2 kinases also contain such motifs on their
N-termini
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
that are absolutely required for MAP2K-MAPK interaction and MAPK activation.
Similarly, both dual-specificity MAP kinase phosphatases and MAP-specific tyrosine phosphatases bind to MAP kinases through the same docking site.
D-motifs can even be found in certain MAPK pathway regulators and scaffolds (e.g. in the mammalian JIP proteins).
Other, less well characterised substrate-binding sites also exist. One such site (the DEF site) is formed by the activation loop (when in the active conformation) and the MAP kinase-specific insert below it. This site can accommodate peptides with an FxFP consensus sequence, typically downstream of the phosphorylation site.
Note that the latter site can only be found in proteins that need to selectively recognize the active MAP kinases, thus they are almost exclusively found in substrates. Different motifs may cooperate with each other, as in the Elk family of transcription factors, that possess both a D-motif and an FxFP motif. The presence of an FxFP motif in the KSR1 scaffold protein also serves to make it an ERK1/2 substrate, providing a negative feedback mechanism to set the correct strength of ERK1/2 activation.
Scaffold proteins
Since the discovery of Ste5 in yeast, scientists were on the hunt to discover similar non-enzymatic scaffolding pathway elements in mammals. There are indeed a number of proteins involved in ERK signaling, that can bind to multiple elements of the pathway:
MP1
MPEG-1 Audio Layer I, commonly abbreviated to MP1, is one of three audio formats included in the MPEG-1 standard. It is a deliberately simplified version of MPEG-1 Audio Layer II (MP2), created for applications where lower compression efficiency ...
binds both MKK1/2 and ERK1/2,
KSR1
Kinase suppressor of Ras 1 is an enzyme that in humans is encoded by the ''KSR1'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' o ...
and
KSR2
The KSR2 gene (also called "The fat gene") is
Kinase suppressor of ras 2 it is a protein that in humans is encoded by the KSR2 gene. KSR2 mutation effects in humans by obesity and because KSR2 gene reduces the ERK signaling and it reduces glucose ...
can bind B-Raf or c-Raf, MKK1/2 and ERK1/2. Analogous proteins were also discovered for the JNK pathway: the
JIP1/
JIP2 and the
JIP3/
JIP4 families of proteins were all shown to bind MLKs, MKK7 and any JNK kinase. Unfortunately, unlike the yeast Ste5, the mechanisms by which they regulate MAPK activation are considerably less understood. While Ste5 actually forms a ternary complex with Ste7 and Fus3 to promote phosphorylation of the latter, known mammalian scaffold proteins appear to work by very different mechanisms. For example, KSR1 and KSR2 are actually MAP3 kinases and related to the Raf proteins.
Although KSRs alone display negligible MAP3 kinase activity, KSR proteins can still participate in the activation of Raf kinases by forming side-to-side heterodimers with them, providing an allosteric pair to turn on each enzymes.
JIPs on the other hand, are apparently transport proteins, responsible for enrichment of MAPK signaling components in certain compartments of polarized cells.
In this context, JNK-dependent phosphorylation of JIP1 (and possibly JIP2) provides a signal for JIPs to release the JIP-bound and inactive upstream pathway components, thus driving a strong local positive feedback loop.
This sophisticated mechanism couples
kinesin-dependent transport to local JNK activation, not only in mammals, but also in the fruitfly ''
Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...
''.
As therapeutic targets
Since the
ERK signaling pathway is involved in both physiological and pathological cell proliferation, it is natural that ERK1/2 inhibitors would represent a desirable class of
antineoplastic agents. Indeed, many of the proto-oncogenic "driver" mutations are tied to ERK1/2 signaling, such as constitutively active (mutant)
receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase ...
s,
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 ...
or
Raf
The Royal Air Force (RAF) is the United Kingdom's air and space force. It was formed towards the end of the First World War on 1 April 1918, becoming the first independent air force in the world, by regrouping the Royal Flying Corps (RFC) and ...
proteins. Although no MKK1/2 or ERK1/2 inhibitors were developed for clinical use, kinase inhibitors that also inhibit
Raf kinases (e.g.
Sorafenib
Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer ( hepatocellular carcinoma), FLT3-ITD positive AML and r ...
) are successful antineoplastic agents against various types of cancer.
MEK inhibitor
Cobimetinib
Cobimetinib, sold under the brand name Cotellic, is an anti-cancer medication used in combination with vemurafenib (Zelboraf) alone or with both vemurafenib and atezolizumab (Tecentriq) to treat melanoma. Cobimetinib is a MEK inhibitor. Cotellic, ...
has been investigated in pre-clinical lung cancer models in combination with inhibition of the
PI3K pathway
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 ...
, where the two drugs lead to a synergistic response.
JNK kinases are implicated in the development of
insulin resistance
Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
in obese individuals
as well as neurotransmitter
excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...
after ischaemic conditions. Inhibition of JNK1 ameliorates insulin resistance in certain animal models. Mice that were genetically engineered to lack a functional JNK3 gene - the major isoform in brain – display enhanced ischemic tolerance and stroke recovery.
Although small-molecule JNK inhibitors are under development, none of them proved to be effective in human tests yet. A peptide-based
JNK inhibitor (AM-111, a retro-inverse D-motif peptide from JIP1, formerly known as XG-102) is also under clinical development for
sensorineural hearing loss
Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve (cranial nerve VIII). SNHL accounts for about 90% of rep ...
.
p38 was once believed to be a perfect target for anti-inflammatory drugs. Yet the failure of more than a dozen chemically different compounds in the clinical phase suggests that p38 kinases might be poor therapeutic targets in
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s. Many of these compounds were found to be
hepatotoxic
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...
to various degree and tolerance to the anti-inflammatory effect developed within weeks.
An alternative approach is to evaluate the potential for targeting upstream MAPKs, such as
ASK1
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and ...
.
Studies in animal models of inflammatory arthritis have yielded promising results, and ASK1 has recently been found to be unique amongst the MAPKs in that it is inducible by inflammatory cytokines such as
TNF-α
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
.
See also
*
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 ...
*
MAP kinase kinase
Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
MAP2K is classified as .
There are seven genes:
* (a.k.a. MEK1)
* (a.k ...
*
MAP kinase kinase kinase
Mitogen Activated Protein (MAP) kinase kinase kinase, MAPKKK (or MAP3K) is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but ar ...
*
MAP kinase kinase kinase kinase Mitogen-activated protein kinase kinase kinase kinase (MAP4K) is a family of proteins involved in cellular signal transduction.
* MAP4K1 (aka HPK1)
* MAP4K2 (aka GCK)
* MAP4K3 (aka GLK)
* MAP4K4 (aka HGK)
* MAP4K5 (aka KHS)
* MAP4K6 (aka MINK)
I ...
*
MAPK1
Mitogen-activated protein kinase 1, (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the ''MAPK1'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracel ...
(ERK2)
*
MAPK3
Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene.
Function
The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) famil ...
(ERK1)
*
MAPK7
Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the ''MAPK7'' gene.
Function
MAPK7 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...
(ERK5)
*
MAPK8
Mitogen-activated protein kinase 8 (also known as JNK1) is a ubiquitous enzyme that in humans is encoded by the ''MAPK8'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase and JNK family. MAP kinases act as an integ ...
(JNK1)
*
MAPK9
Mitogen-activated protein kinase 9 is an enzyme that in humans is encoded by the ''MAPK9'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical s ...
(JNK2)
*
MAPK10
Mitogen-activated protein kinase 10 also known as c-Jun N-terminal kinase 3 (JNK3) is an enzyme that in humans is encoded by the ''MAPK10'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as ...
(JNK3)
*
MAPK11
Mitogen-activated protein kinase 11 is an enzyme that in humans is encoded by the ''MAPK11'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...
(p38-beta)
*
MAPK12
Mitogen-activated protein kinase 12 (MAP kinase 12), also known as extracellular signal-regulated kinase 6 (ERK6) or stress-activated protein kinase 3 (SAPK3), is an enzyme that in humans is encoded by the ''MAPK12'' gene.
Function
Activation o ...
(p38-gamma)
*
MAPK13
Mitogen-activated protein kinase 13 (MAPK 13), also known as stress-activated protein kinase 4 (SAPK4), is an enzyme that in humans is encoded by the ''MAPK13'' gene.
Function
The protein encoded by this gene is a member of the MAP kinase fami ...
(p38-delta)
*
MAPK14
Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the ''MAPK14'' gene.
MAPK14 encodes p38α mitogen-activated protein kinase (MAPK) which is the prototypic member of the p38 MAPK family. p38 MAPKs ...
(p38-alpha)
*
MAPK4
Mitogen-activated protein kinase 4 is an enzyme that in humans is encoded by the ''MAPK4'' gene.
Mitogen-activated protein kinase 4 is a member of the mitogen-activated protein kinase family. Tyrosine kinase growth factor receptors activate mitoge ...
(ERK4: atypical MAPK)
*
MAPK6
Mitogen-activated protein kinase 6 is an enzyme that in humans is encoded by the ''MAPK6'' gene.
The protein encoded by this gene is a member of the Ser/Thr protein kinase family, and is most closely related to mitogen-activated protein kinases ( ...
(ERK3: atypical MAPK)
*
MAPK15
Mitogen-activated protein kinase 15, also known as MAPK15, ERK7, or ERK8, is an enzyme that in humans is encoded by the ''MAPK15'' gene.
Evolutionarily, MAPK15 is conserved in a number of species, including '' P. troglodytes'', '' B. taurus'', '' ...
(ERK7/ERK8: atypical MAPK)
*
NLK
Serine/threonine protein kinase NLK is an enzyme that in humans is encoded by the ''NLK'' gene. Its name is an abbreviation for ''Nemo-Like Kinase'', Nemo (nmo) being the ''Drosophila'' ortholog
Sequence homology is the biological homology b ...
(Nemo-like kinase: atypical MAPK)
*
ERK1/2 kinases
*
ERK1/2 pathway
*
JNK kinases
*
p38 MAP kinases
p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differe ...
*
MEKK2 (MAP3K2)
*
ASK1
Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and ...
(MAP3K5)
References
External links
MAP Kinase Resource
for mitogen-activated kinases.
*
Model of MAPK ultrasensitivity in BioModels Database
{{Portal bar, Biology, border=no
Protein kinases
Signal transduction
EC 2.7.11
Aging-related enzymes
Anti-aging substances