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.

Main article: Mitogen-activated protein kinase

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.

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
SymbolMAPK1
Alt. symbolsPRKM2, PRKM1
NCBI gene5594
HGNC6871
OMIM176948
RefSeqNM_002745
UniProtP28482
Other data
LocusChr. 22 q11.2

Mitogen-activated protein kinase 1 (MAPK1) is also known as "extracellular signal-regulated kinase 2" (ERK2). Two similar (85% sequence identity) protein kinases 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] Apart from developmental defects, under activity or lack of MAPK1 (Erk2) resist activation induced cell death in helper T cells which could cause autoimmunity due to T helper 17 persistence.[8]

Mitogen-activated protein kinase 3
See also: MAPK3
mitogen-activated protein kinase 3
Identifiers
SymbolMAPK3
Alt. symbolsPRKM3
NCBI gene5595
HGNC6877
OMIM601795
RefSeqNM_001040056
UniProtP27361
Other data
LocusChr. 16 p11.2

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 most MAPK3 functions in most cells.[9] The main exception is in T cells. Mice lacking MAPK3 have reduced T cell development past the CD4+CD8+ stage.

Clinical significance

Activation of the ERK1/2 pathway by aberrant RAS/RAF signalling, DNA damage, and oxidative stress leads to cellular senescence.[10] 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.[10]

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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. doi:10.1038/358417a0. PMID 1322500.
  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. 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. 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. doi:10.1073/pnas.2134254100. PMC 240691. PMID 14566055.
  8. Peroumal D, Abimannan T, Tagirasa R, Parida JR, Singh SK, Padhan P, Devadas S (July 2016). "Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance". Oncotarget. 7 (34): 54339–54359. doi:10.18632/oncotarget.10913. PMC 5342346. PMID 27486885.
  9. 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.
  10. 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.
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