Extracellular signal-regulated kinases

Main article: Mitogen-activated protein kinase

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]}

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]}

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,^[1] 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

See also: MAPK1

mitogen-activated protein kinase 1
Identifiers
Symbol	MAPK1
Alt. symbols	PRKM2, PRKM1
NCBI gene	5594
HGNC	6871
OMIM	176948
RefSeq	NM_002745
UniProt	P28482
Other data
Locus	Chr. 22 q11.2
Search for Structures Swiss-model Domains InterPro

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.^[2] 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.^[3] Another protein kinase, Raf-1, was shown to phosphorylate a "MAP kinase-kinase", thus qualifying as a "MAP kinase kinase kinase".^[4] The MAP kinase-kinase, which activates ERK, was named "MAPK/ERK kinase" (MEK).^[5]

Receptor-linked tyrosine kinases, Ras, Raf, MEK, and MAPK could be fitted into a signaling cascade linking an extracellular signal to MAPK activation.^[6] See: MAPK/ERK pathway.

Transgenic gene knockout mice lacking MAPK1 have major defects in early development.^[7] Conditional deletion of Mapk1 in B cells showed a role for MAPK1 in T-cell-dependent antibody production.^[8] A dominant gain-of-function mutant of Mapk1 in transgenic mice showed a role for MAPK1 in T-cell development.^[9] 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.^[10]

Mitogen-activated protein kinase 3

See also: MAPK3

mitogen-activated protein kinase 3
Identifiers
Symbol	MAPK3
Alt. symbols	PRKM3
NCBI gene	5595
HGNC	6877
OMIM	601795
RefSeq	NM_001040056
UniProt	P27361
Other data
Locus	Chr. 16 p11.2
Search for Structures Swiss-model Domains InterPro

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.^[11] The main exception is in T cells. Mice lacking MAPK3 have reduced T cell development past the CD4+ and CD8+ stage.

Clinical significance

Activation of the ERK1/2 pathway by aberrant RAS/RAF signalling, DNA damage, and oxidative stress leads to cellular senescence.^[12] 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.^[12]

References

1. Rao VN, Reddy ES (July 1994). "elk-1 proteins interact with MAP kinases". Oncogene. 9 (7): 1855–60. PMID 8208531.
2. Boulton TG, Cobb MH (May 1991). "Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies". Cell Regulation. 2 (5): 357–71. doi:10.1091/mbc.2.5.357. PMC 361802. PMID 1654126.
3. Leevers SJ, Marshall CJ (February 1992). "Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein". The EMBO Journal. 11 (2): 569–74. doi:10.1002/j.1460-2075.1992.tb05088.x. PMC 556488. PMID 1371463.
4. Kyriakis JM, App H, Zhang XF, Banerjee P, Brautigan DL, Rapp UR, Avruch J (July 1992). "Raf-1 activates MAP kinase-kinase". Nature. 358 (6385): 417–21. Bibcode:1992Natur.358..417K. doi:10.1038/358417a0. PMID 1322500. S2CID 4335307.
5. Crews CM, Erikson RL (September 1992). "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". Proceedings of the National Academy of Sciences of the United States of America. 89 (17): 8205–9. Bibcode:1992PNAS...89.8205C. doi:10.1073/pnas.89.17.8205. PMC 49886. PMID 1381507.
6. Itoh T, Kaibuchi K, Masuda T, Yamamoto T, Matsuura Y, Maeda A, Shimizu K, Takai Y (February 1993). "A protein factor for ras p21-dependent activation of mitogen-activated protein (MAP) kinase through MAP kinase kinase". Proceedings of the National Academy of Sciences of the United States of America. 90 (3): 975–9. Bibcode:1993PNAS...90..975I. doi:10.1073/pnas.90.3.975. PMC 45793. PMID 8381539.
7. Yao Y, Li W, Wu J, Germann UA, Su MS, Kuida K, Boucher DM (October 2003). "Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation". Proceedings of the National Academy of Sciences of the United States of America. 100 (22): 12759–64. Bibcode:2003PNAS..10012759Y. doi:10.1073/pnas.2134254100. PMC 240691. PMID 14566055.
8. Sanjo, Hideki; Hikida, Masaki; Aiba, Yuichi; Mori, Yoshiko; Hatano, Naoya; Ogata, Masato; Kurosaki, Tomohiro (2007). "Extracellular signal-regulated protein kinase 2 is required for efficient generation of B cells bearing antigen-specific immunoglobulin G". Molecular and Cellular Biology. 27 (4): 1236–1246. doi:10.1128/MCB.01530-06. ISSN 0270-7306. PMC 1800707. PMID 17145771.
9. Sharp, L. L.; Schwarz, D. A.; Bott, C. M.; Marshall, C. J.; Hedrick, S. M. (1997). "The influence of the MAPK pathway on T cell lineage commitment". Immunity. 7 (5): 609–618. doi:10.1016/s1074-7613(00)80382-9. ISSN 1074-7613. PMID 9390685.
10. Samuels, Ivy S.; Karlo, J. Colleen; Faruzzi, Alicia N.; Pickering, Kathryn; Herrup, Karl; Sweatt, J. David; Saitta, Sulagna C.; Landreth, Gary E. (2008-07-02). "Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function". The Journal of Neuroscience. 28 (27): 6983–6995. doi:10.1523/JNEUROSCI.0679-08.2008. ISSN 1529-2401. PMC 4364995. PMID 18596172.
11. Pagès G, Guérin S, Grall D, Bonino F, Smith A, Anjuere F, Auberger P, Pouysségur J (November 1999). "Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice". Science. 286 (5443): 1374–7. doi:10.1126/science.286.5443.1374. PMID 10558995.
12. Anerillas C, Abdelmohsen K, Gorospe M (2020). "Regulation of senescence traits by MAPKs". GeroScience. 42 (2): 397–408. doi:10.1007/s11357-020-00183-3. PMC 7205942. PMID 32300964.

External links

• The Extracellular Signal-Regulated Kinases
• MAP Kinase Resource 2021-04-15 at the Wayback Machine.
• Extracellular+Signal-Regulated+MAP+Kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Info with links in the Cell Migration Gateway 2014-12-11 at the Wayback Machine