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 postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.{{Citation needed|date=February 2007}}

The term, "extracellular signal-regulated kinases", is sometimes used as a synonym for mitogen-activated protein kinase (MAPK), but has more recently been adopted for a specific subset of the mammalian MAPK family.{{citation needed|date=May 2016}}

In the MAPK/ERK pathway, Ras activates c-Raf, followed by mitogen-activated protein kinase kinase (abbreviated as MKK, MEK, or MAP2K) and then MAPK1/2 (below). Ras is typically activated by growth hormones through receptor tyrosine kinases and GRB2/SOS, but may also receive other signals. ERKs are known to activate many transcription factors, such as ELK1,{{cite journal | vauthors = Rao VN, Reddy ES | title = elk-1 proteins interact with MAP kinases | journal = Oncogene | volume = 9 | issue = 7 | pages = 1855–60 | date = July 1994 | pmid = 8208531 }} and some downstream protein kinases.

Disruption of the ERK pathway is common in cancers, especially Ras, c-Raf, and receptors such as HER2.

Mitogen-activated protein kinase 1

{{infobox protein | Name = mitogen-activated protein kinase 1 | caption = | image = | width = | HGNCid = 6871 | Symbol = MAPK1 | AltSymbols = PRKM2, PRKM1 | EntrezGene = 5594 | OMIM = 176948 | RefSeq = NM_002745 | UniProt = P28482 | PDB = | ECnumber = | Chromosome = 22 | Arm = q | Band = 11.2 | LocusSupplementaryData = }}

Mitogen-activated protein kinase 1 (MAPK1) is also known as extracellular signal-regulated kinase 2 (ERK2). Two similar protein kinases with 85% sequence identity were originally called ERK1 and ERK2.{{cite journal | vauthors = Boulton TG, Cobb MH | title = Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies | journal = Cell Regulation | volume = 2 | issue = 5 | pages = 357–71 | date = May 1991 | pmid = 1654126 | pmc = 361802 | doi = 10.1091/mbc.2.5.357 }} They were found during a search for protein kinases that are rapidly phosphorylated after activation of cell surface tyrosine kinases such as the epidermal growth factor receptor. Phosphorylation of ERKs leads to the activation of their kinase activity.

The molecular events linking cell surface receptors to activation of ERKs are complex. It was found that Ras GTP-binding proteins are involved in the activation of ERKs.{{cite journal | vauthors = Leevers SJ, Marshall CJ | title = Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein | journal = The EMBO Journal | volume = 11 | issue = 2 | pages = 569–74 | date = February 1992 | pmid = 1371463 | pmc = 556488 | doi = 10.1002/j.1460-2075.1992.tb05088.x }} Another protein kinase, Raf-1, was shown to phosphorylate a "MAP kinase-kinase", thus qualifying as a "MAP kinase kinase kinase".{{cite journal | vauthors = Kyriakis JM, App H, Zhang XF, Banerjee P, Brautigan DL, Rapp UR, Avruch J | title = Raf-1 activates MAP kinase-kinase | journal = Nature | volume = 358 | issue = 6385 | pages = 417–21 | date = July 1992 | pmid = 1322500 | doi = 10.1038/358417a0 | bibcode = 1992Natur.358..417K | s2cid = 4335307 }} The MAP kinase-kinase, which activates ERK, was named "MAPK/ERK kinase" (MEK).{{cite journal | vauthors = Crews CM, Erikson RL | title = Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 17 | pages = 8205–9 | date = September 1992 | pmid = 1381507 | pmc = 49886 | doi = 10.1073/pnas.89.17.8205 | bibcode = 1992PNAS...89.8205C | doi-access = free }}

Receptor-linked tyrosine kinases, Ras, Raf, MEK, and MAPK could be fitted into a signaling cascade linking an extracellular signal to MAPK activation.{{cite journal | vauthors = Itoh T, Kaibuchi K, Masuda T, Yamamoto T, Matsuura Y, Maeda A, Shimizu K, Takai Y | title = A protein factor for ras p21-dependent activation of mitogen-activated protein (MAP) kinase through MAP kinase kinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 3 | pages = 975–9 | date = February 1993 | pmid = 8381539 | pmc = 45793 | doi = 10.1073/pnas.90.3.975 | bibcode = 1993PNAS...90..975I | doi-access = free }} See: MAPK/ERK pathway.

Transgenic gene knockout mice lacking MAPK1 have major defects in early development.{{cite journal | vauthors = Yao Y, Li W, Wu J, Germann UA, Su MS, Kuida K, Boucher DM | title = Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 22 | pages = 12759–64 | date = October 2003 | pmid = 14566055 | pmc = 240691 | doi = 10.1073/pnas.2134254100 | bibcode = 2003PNAS..10012759Y | doi-access = free }} Conditional deletion of Mapk1 in B cells showed a role for MAPK1 in T-cell-dependent antibody production.{{Cite journal|last1=Sanjo|first1=Hideki|last2=Hikida|first2=Masaki|last3=Aiba|first3=Yuichi|last4=Mori|first4=Yoshiko|last5=Hatano|first5=Naoya|last6=Ogata|first6=Masato|last7=Kurosaki|first7=Tomohiro|date=2007|title=Extracellular signal-regulated protein kinase 2 is required for efficient generation of B cells bearing antigen-specific immunoglobulin G|journal=Molecular and Cellular Biology|volume=27|issue=4|pages=1236–1246|doi=10.1128/MCB.01530-06|issn=0270-7306|pmc=1800707|pmid=17145771}} A dominant gain-of-function mutant of Mapk1 in transgenic mice showed a role for MAPK1 in T-cell development.{{Cite journal|last1=Sharp|first1=L. L.|last2=Schwarz|first2=D. A.|last3=Bott|first3=C. M.|last4=Marshall|first4=C. J.|last5=Hedrick|first5=S. M.|date=1997|title=The influence of the MAPK pathway on T cell lineage commitment|journal=Immunity|volume=7|issue=5|pages=609–618|doi=10.1016/s1074-7613(00)80382-9|issn=1074-7613|pmid=9390685|doi-access=free}} Conditional inactivation of Mapk1 in neural progenitor cells of the developing cortex lead to a reduction of cortical thickness and reduced proliferation in neural progenitor cells.{{Cite journal|last1=Samuels|first1=Ivy S.|last2=Karlo|first2=J. Colleen|last3=Faruzzi|first3=Alicia N.|last4=Pickering|first4=Kathryn|last5=Herrup|first5=Karl|last6=Sweatt|first6=J. David|last7=Saitta|first7=Sulagna C.|last8=Landreth|first8=Gary E.|date=2008-07-02|title=Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function|journal=The Journal of Neuroscience|volume=28|issue=27|pages=6983–6995|doi=10.1523/JNEUROSCI.0679-08.2008|issn=1529-2401|pmc=4364995|pmid=18596172}}

Mitogen-activated protein kinase 3

{{infobox protein | Name = mitogen-activated protein kinase 3 | caption = | image = | width = | HGNCid = 6877 | Symbol = MAPK3 | AltSymbols = PRKM3 | EntrezGene = 5595 | OMIM = 601795 | RefSeq = NM_001040056 | UniProt = P27361 | PDB = | ECnumber = | Chromosome = 16 | Arm = p | Band = 11.2 | LocusSupplementaryData = }}

Mitogen-activated protein kinase 3 (MAPK3) is also known as extracellular signal-regulated kinase 1 (ERK1). Transgenic gene knockout mice lacking MAPK3 are viable and it is thought that MAPK1 can fulfill some MAPK3 functions in most cells.{{cite journal | vauthors = Pagès G, Guérin S, Grall D, Bonino F, Smith A, Anjuere F, Auberger P, Pouysségur J | title = Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice | journal = Science | volume = 286 | issue = 5443 | pages = 1374–7 | date = November 1999 | pmid = 10558995 | doi = 10.1126/science.286.5443.1374 }} The main exception is in T cells. Mice lacking MAPK3 have reduced T cell development past the CD4+ and CD8+ stage.

Mitogen-activated protein kinase 7

Mitogen-activated protein kinase 7 (MAPK7) is also known as extracellular signal-regulated kinase 5 (ERK5). Sometimes referred to as Big MAPK or BMK due to its large size in comparison to other MAPKs.{{Cite web |title=MAPK7 mitogen-activated protein kinase 7 [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/5598 |access-date=2025-04-03 |website=www.ncbi.nlm.nih.gov}}

Clinical significance

Activation of the ERK1/2 pathway by aberrant RAS/RAF signalling, DNA damage, and oxidative stress leads to cellular senescence.{{cite journal | vauthors = Anerillas C, Abdelmohsen K, Gorospe M | title = Regulation of senescence traits by MAPKs | journal = GeroScience | volume = 42 | issue=2 | pages = 397–408 | date=2020 | doi = 10.1007/s11357-020-00183-3 | pmc=7205942 | pmid = 32300964}} Low doses of DNA damage resulting from cancer therapy cause ERK1/2 to induce senescence, whereas higher doses of DNA damage fail to activate ERK1/2, and thus induce cell death by apoptosis.

References

External links

{{usurped|1=[https://web.archive.org/web/20090123022346/http://macromoleculeinsights.com/erk.php The Extracellular Signal-Regulated Kinases]}}
[http://www.mapkinases.eu MAP Kinase Resource ] {{Webarchive|url=https://web.archive.org/web/20210415072533/http://www.mapkinases.eu/ |date=2021-04-15 }}.
{{MeshName|Extracellular+Signal-Regulated+MAP+Kinases}}
[https://web.archive.org/web/20110704223802/http://cmkb.cellmigration.org/report.cgi?report=orth_overview&gene_id=5594 MAPK1]
[https://web.archive.org/web/20110722013330/http://cmkb.cellmigration.org/report.cgi?report=orth_overview&gene_id=5595 MAPK3] Info with links in the [http://www.cellmigration.org/index.shtml Cell Migration Gateway] {{Webarchive|url=https://web.archive.org/web/20141211173306/http://www.cellmigration.org/index.shtml |date=2014-12-11 }}

Category:Signal transduction

Category:Mitogen-activated protein kinases

Category:EC 2.7.11