![MAPKpathway diagram](https://upload.wikimedia.org/wikipedia/commons/1/11/MAPKpathway_diagram.svg)
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
in the
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
that communicates a signal from a
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
on the surface of the cell to the
DNA in the nucleus of the cell.
The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as
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 ...
. The pathway includes many proteins, such as
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 ...
s (MAPKs), originally called
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), which communicate by adding phosphate groups to a neighboring protein (
phosphorylating
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, whi ...
it), thereby acting as an "on" or "off" switch.
When one of the proteins in the pathway is mutated, it can become stuck in the "on" or "off" position, a necessary step in the development of many cancers. In fact, components of the MAPK/ERK pathway were first discovered in cancer cells, and drugs that reverse the "on" or "off" switch are being investigated as cancer treatments.
Background
The signal that starts the MAPK/ERK pathway is the binding of extracellular
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 ...
to a
cell surface receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...
. This allows a
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 ...
protein (a
Small GTPase
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 heterotri ...
) to swap a
GDP
Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is often ...
molecule for a
GTP molecule, flipping the "on/off switch" of the pathway. The Ras protein can then activate
MAP3K (e.g.,
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 ...
), which activates
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 ...
, which activates
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 ...
. Finally, MAPK can activate a
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 ...
, such as
Myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...
. This process is described in more detail below.
Ras activation
Receptor-linked
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 ...
s, such as the
epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor recept ...
(EGFR), are activated by extracellular
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 ...
s, such as the
epidermal growth factor
Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds.
EGF was originally descr ...
(EGF). Binding of EGF to the EGFR activates the tyrosine kinase activity of the
cytoplasmic domain of the receptor. The EGFR becomes
phosphorylated
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, whi ...
on tyrosine residues. Docking proteins such as
GRB2 contain an
SH2 domain
The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosphory ...
that binds to the phosphotyrosine residues of the activated receptor.
GRB2 binds to the
guanine nucleotide exchange factor
Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structu ...
SOS
is a Morse code distress signal (), used internationally, that was originally established for maritime use. In formal notation is written with an overscore line, to indicate that the Morse code equivalents for the individual letters of "SOS" ...
by way of the two
SH3 domain
The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phos ...
s of GRB2. When the GRB2-SOS complex docks to phosphorylated EGFR, SOS becomes activated.
Activated SOS then promotes the removal of
GDP
Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is often ...
from a member of the
Ras subfamily
Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals ...
(most notably
H-Ras
GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 t ...
or
K-Ras
''KRAS'' (Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell ...
). The Ras protein can then bind
GTP and become active.
Apart from EGFR, other cell surface receptors that can activate this pathway via GRB2 include
Trk A/B,
Fibroblast growth factor receptor
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of ...
(FGFR) and
PDGFR
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular ...
.
Kinase cascade
Activated Ras then activates the protein kinase activity of a
RAF kinase.
The RAF kinase phosphorylates and activates a
MAPK/ERK Kinase (
MEK1
Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the ''MAP2K1'' gene.
Function
The protein encoded by this gene is a member of the dual-specificity protein kinase family that acts as a mito ...
or
MEK2
Dual specificity mitogen-activated protein kinase kinase 2 is an enzyme that in humans is encoded by the ''MAP2K2'' gene. It is more commonly known as MEK2, but has many alternative names including CFC4, MKK2, MAPKK2 and PRKMK2.
Function
The ...
). The MEK phosphorylates and activates a
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 ...
(MAPK).
RAF and MAPK/ERK are both
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 ...
s. MEK is a serine/tyrosine/threonine kinase.
In a technical sense, RAF, MEK, and MAPK are all
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 ...
-activated kinases, as is MNK (see below). MAPKs were originally called "
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) and "microtubule associated protein kinases" (MAPKs). One of the first proteins known to be phosphorylated by ERK was a
microtubule-associated protein In cell biology, microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton. MAPs are integral to: the stability of the cell and its internal structures and the transport of components within ...
(MAP). As discussed below, many additional targets for phosphorylation by MAPK were later found, and the protein was renamed "mitogen-activated protein kinase" (MAPK). The series of kinases from RAF to MEK to MAPK is an example of a protein kinase
cascade
Cascade, Cascades or Cascading may refer to:
Science and technology Science
*Cascade waterfalls, or series of waterfalls
* Cascade, the CRISPR-associated complex for antiviral defense (a protein complex)
* Cascade (grape), a type of fruit
* Bioc ...
. Such series of kinases provide opportunities for
feedback
Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause-and-effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handled ...
regulation and signal amplification.
Regulation of translation and transcription
Three of the many proteins that are phosphorylated by MAPK are shown in the figure to the right. One effect of MAPK activation is to alter the
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
of
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
to proteins. MAPK phosphorylates the 40S
ribosomal
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to fo ...
protein
S6 kinase (RSK). This activates RSK, which, in turn, phosphorylates
ribosomal protein S6
Ribosomal protein S6 (rpS6 or eS6) is a component of the 40S ribosomal subunit and is therefore involved in translation. Mouse model studies have shown that phosphorylation of eS6 is involved in the regulation of cell size, cell proliferation, and ...
.
Mitogen-activated protein kinases that phosphorylate ribosomal protein S6 were the first to be isolated.
[
MAPK regulates the activities of several ]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 ...
s. MAPK can phosphorylate C-myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...
. MAPK phosphorylates and activates MNK, which, in turn, phosphorylates CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
. MAPK also regulates the transcription of the C-Fos
Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jinkin ...
gene. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for 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 ...
.
The 22q11, 1q42, and 19p13 genes, by affecting the ERK pathway, are associated with schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
, schizoaffective disorder
Schizoaffective disorder (SZA, SZD or SAD) is a mental disorder characterized by abnormal thought processes and an unstable mood. This diagnosis is made when the person has symptoms of both schizophrenia (usually psychosis) and a mood disorder: ...
, bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
, and migraines
Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
.
Regulation of cell cycle entry and proliferation
Role of mitogen signaling in cell cycle progression
The ERK pathway plays an important role of integrating external signals from the presence of mitogens such as epidermal growth factor (EGF) into signaling events promoting cell growth and proliferation in many mammalian cell types. In a simplified model, the presence of mitogens and growth factors trigger the activation of canonical receptor tyrosine kinases such as EGFR leading to their dimerization and subsequent activation of the small GTPase Ras.[Meloche, et al.. “The ERK1/2 Mitogen-Activated Protein Kinase Pathway as a Master Regulator of the G1- to S-Phase Transition.” Oncogene, vol. 26, no. 22, 2007, pp. 3227–3239., .] This then leads to a series of phosphorylation events downstream in the MAPK cascade (Raf-MEK-ERK) ultimately resulting in the phosphorylation and activation of ERK. The phosphorylation of ERK results in an activation of its kinase activity and leads to phosphorylation of its many downstream targets involved in regulation of cell proliferation. In most cells, some form of sustained ERK activity is required for cells to activate genes that induce cell cycle entry and suppress negative regulators of the cell cycle. Two such important targets include Cyclin D complexes with Cdk4 and Cdk6 (Cdk4/6) which are both phosphorylated by ERK.[Chambard, Jean-Claude, et al. “ERK Implication in Cell Cycle Regulation.” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol. 1773, no. 8, 2007, pp. 1299–1310., .] The transition from G1 to S phase is coordinated by the activity of Cyclin D-Cdk4/6, which increases during late G1 phase as cells prepare to enter S-phase in response to mitogens. Cdk4/6 activation contributes to hyper-phosphorylation and the subsequent destabilization of retinoblastoma protein (Rb). Hypo-phosphorylated Rb, is normally bound to transcription factor E2F in early G1 and inhibits its transcriptional activity, preventing expression of S-phase entry genes including Cyclin E, Cyclin A2 and Emi1. ERK1/2 activation downstream of mitogen induced Ras signaling is necessary and sufficient to remove this cell cycle block and allow cells to progress to S-phase in most mammalian cells.
Downstream feedback control and generation of a bistable G1/S switch
The restriction point (R-point) marks the critical event when a mammalian cell commits to proliferation and becomes independent of growth stimulation. It is fundamental for normal differentiation and tissue homeostasis, and seems to be dysregulated in virtually all cancers. Although the R-point has been linked to various activities involved in the regulation of G1–S transition of the mammalian cell cycle, the underlying mechanism remains unclear. Using single-cell measurements, Yao et al., shows that the Rb–E2F pathway functions as a bistable switch to convert graded serum inputs into all-or-none E2F responses.
Growth and mitogen signals are transmitted downstream of the ERK pathway are incorporated into multiple positive feedback loops to generate a bistable switch at the level of E2F activation.[4. Yao, Guang, et al. “A Bistable Rb-E2F Switch Underlies the Restriction Point.” Nature Cell Biology, vol. 10, no. 4, 2008, pp. 476–482., .] This occurs due to three main interactions during late G1 phase. The first is a result of mitogen stimulation though the ERK leading to the expression of the transcription factor Myc, which is a direct activator of E2F. The second pathway is a result of ERK activation leading to the accumulation of active complexes of Cyclin D and Cdk4/6 which destabilize Rb via phosphorylation and further serve to activate E2F and promote expression of its targets. Finally, these interactions are all reinforced by an additional positive feedback loop by E2F on itself, as its own expression leads to production of the active complex of Cyclin E and CDK2, which further serves to lock in a cell's decision to enter S-phase. As a result, when serum concentration is increased in a gradual manner, most mammalian cells respond in a switch-like manner in entering S-phase. This mitogen stimulated, bistable E2F switch is exhibits hysteresis, as cells are inhibited from returning to G1 even after mitogen withdrawal post E2F activation.[Yao, Guang, et al. “A Bistable Rb-E2F Switch Underlies the Restriction Point.” Nature Cell Biology, vol. 10, no. 4, 2008, pp. 476–482., .]
Dynamic signal processing by the ERK pathway
The EGFR-ERK/MAPK (epidermal growth factor receptor extracellular-regulated kinase/mitogen-activated protein kinase) pathway stimulated by EGF is critical for cellular proliferation, but the temporal separation between signal and response obscures the signal-response relationship in previous research.In 2013, Albeck et al. provided key experimental evidence to fill this gap of knowledge. They measured signal strength and dynamics with steady-state EGF stimulation, in which the signaling and output can be easily related. They further mapped the signal-response relationship across the pathway’s full dynamic range. Using high-content immunofluorescence (HCIF) detection of phosphorylated ERK (pERK) and live cell FRET biosensors, they monitored downstream output of the ERK pathway in both live cells and fixed cells. To further link the quantitative characteristics of ERK signaling to proliferation rates, they established a series of steady-state conditions using a range of EGF concentrations by applying EGF with different concentrations.
Single cell imaging experiments have shown ERK to be activated in stochastic bursts in the presence of EGF. Furthermore, the pathway has been shown to encode the strength of signaling inputs though frequency modulated pulses of its activity. Using live cell FRET biosensors, cells induced with different concentrations of EGF illicit activity bursts of different frequency, where higher levels of EGF resulted in more frequent bursts of ERK activity. To figure out how S phase entry can be affected by sporadic pulses of ERK activity at low EGF concentrations, they used MCF-10A cells co-expressing EKAR-EV and RFP-geminin and identified the pulses of ERK activity with the scoring and then align this ERK activity profiles with time of GFP-geminin induction. They found that longer periods of ERK activity stimulate S phase entry, as suggested by increased pulse length. To understand the dynamics of EGFR-ERK pathway, specifically how is the frequency and amplitude modulated, they applied the EGFR inhibitor gefitinib or the highly selective MAPK/ERK kinase (MEK) inhibitor PD0325901 (PD). Two inhibitors yield actually a little bit different result: gefitinib, at intermediate concentration, would induce pulsatory behavior and also bimodal shift, which is not observed with PD. They further combine EGF and PD together and draw the conclusion that the frequency of ERK activities is modulated by quantitative variation while the amplitude is modulated by MEK activity’s change. Lastly they turned to Fra-1, one of downstream effectors of ERK pathway, as it’s technically challenging to estimate ERK activities directly. To understand how the integrated ERK pathway output (which should be independent of either frequency or amplitude) affect the proliferation rate, they used the combination of a wide range of EGF and PD concentrations and find that there’s actually an inverted “L” shape single curvilinear relationship, which suggests that at low levels of ERK pathway output, small changes in signal intensity correspond to large changes in proliferative rate, while large changes in signal intensity near the high end of the dynamic range have little impact on proliferation. The fluctuation of ERK signaling highlights potential issues with current therapeutic approaches, providing new perspective in terms of thinking about drug targeting in the ERK pathway in cancer.
Integration of mitogen and stress signals in proliferation
Recent live cell imaging experiments in MCF10A and MCF7 cells have shown that a combination of mitogen signaling though ERK and stress signals through activation of p53 in mother cells contributes to the likelihood of whether newly formed daughter cells will immediately re-enter the cell cycle or enter quiescence (G0) preceding mitosis. Rather than daughter cells starting with no key signaling proteins after division, mitogen/ERK induced Cyclin D1 mRNA and DNA damage induced p53 protein, both long lived factors in cells, can be stably inherited from mother cells after cell division. The levels of these regulators vary from cell to cell after mitosis and stoichiometry between them strongly influences cell cycle commitment though activation of Cdk2. Chemical perturbations using inhibitors of ERK signaling or inducers p53 signaling in mother cells suggest daughter cells with high levels of p53 protein and low levels of Cyclin D1 transcripts were shown to primarily enter G0 whereas cells with high Cyclin D1 and low levels of p53 are most likely to reenter the cell cycle. These results illustrate a form of encoded molecular memory though the history of mitogen signaling through ERK and stress response though p53.
Clinical significance
Uncontrolled growth is a necessary step for the development of all cancers. In many cancers (e.g. melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
), a defect in the MAP/ERK pathway leads to that uncontrolled growth. Many compounds can inhibit steps in the MAP/ERK pathway, and therefore are potential drugs for treating cancer,
e.g., Hodgkin disease
Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition wa ...
.
The first drug licensed to act on this pathway is 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 ...
— a 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 ...
kinase inhibitor.
Other Raf inhibitors: SB590885, PLX4720, XL281, RAF265, encorafenib
Encorafenib, sold under the brand name Braftovi, is a medication for the treatment of certain melanoma cancers. It is a small molecule BRAF inhibitor that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different ...
, dabrafenib
Dabrafenib, sold under the brand name Tafinlar & Rafinlar ( both by Novartis) among others, is a medication for the treatment of cancers associated with a mutated version of the gene BRAF. Dabrafenib acts as an inhibitor of the associated enzym ...
, vemurafenib
Vemurafenib (INN, marketed as Zelboraf) is an inhibitor of the B-Raf enzyme developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech for the treatment of late-stage melanoma.; The name "vemurafenib" comes from V600E mutated BRAF in ...
.[
Some ]MEK inhibitor A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2.
They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers. (See MAPK/ERK pathway#Clinical sign ...
s: 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, ...
, CI-1040, PD0325901, Binimetinib
Binimetinib, also known as Mektovi and ARRY-162, is an anti-cancer small molecule that was developed by Array Biopharma to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. ...
(MEK162
Binimetinib, also known as Mektovi and ARRY-162, is an anti-cancer small molecule that was developed by Array Biopharma to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK/ERK pathw ...
), selumetinib
Selumetinib ( ), sold under the brand name Koselugo, is a medication for the treatment of children, two years of age and older, with neurofibromatosis type I (NF-1), a genetic disorder of the nervous system causing tumors to grow on nerves. It ...
,[ ]Trametinib
Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma. It is a MEK inhibitor drug with anti-cancer activity. It inhibits MEK1 and MEK2.
Trametinib had good results for metast ...
(GSK1120212) It has been found that acupoint-moxibustion has a role in relieving alcohol-induced gastric mucosal injury in a mouse model, which may be closely associated with its effects in up-regulating activities of the epidermal growth factor/ERK signal transduction pathway.
RAF-ERK pathway is also involved in the pathophysiology of Noonan's Syndrome
Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored ...
, a polymalformative disease, where Simvastatin was proposed as a way to improve CNS-cognitive symptoms of the disorder.
Protein microarray analysis can be used to detect subtle changes in protein activity in signaling pathways.[
] The developmental syndromes caused by germline mutations in genes that alter the RAS components of the MAP/ERK signal transduction pathway are called RASopathies.
See also
*Janus kinase
Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoveries ...
*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 ...
*Signal transducing adaptor protein
Signal transducing adaptor proteins (STAPs) are proteins that are accessory to main proteins in a signal transduction pathway. Adaptor proteins contain a variety of protein-binding modules that link protein-binding partners together and facilitat ...
*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 ...
References
External links
MAP Kinase Resource
*Kyoto Encyclopedia of Genes and Genomes
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 analysi ...
MAPK pathway
*
{{DEFAULTSORT:MAPK ERK pathway
Signal transduction
Cell signaling