Extracellular signal-regulated kinases

Last updated

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 ]

Contents

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

mitogen-activated protein kinase 1
Identifiers
Symbol MAPK1
Alt. symbolsPRKM2, 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

mitogen-activated protein kinase 3
Identifiers
Symbol MAPK3
Alt. symbolsPRKM3
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]

Related Research Articles

A mitogen-activated protein kinase is a type of protein kinase that is specific to the amino acids serine and threonine. MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.

<span class="mw-page-title-main">Restriction point</span> Animal cell cycle checkpoint

The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint in the G1 phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G1/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2-M DNA damage checkpoint and the spindle checkpoint.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

Mitogen Activated Protein (MAP) kinase kinase kinase 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 are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

<span class="mw-page-title-main">RAF kinase</span>

RAF kinases are a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes. The mouse sarcoma virus 3611 contains a RAF kinase-related oncogene that enhances fibrosarcoma induction. RAF is an acronym for Rapidly Accelerated Fibrosarcoma.

<span class="mw-page-title-main">MAPK1</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 1, also known as ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.

<span class="mw-page-title-main">MAPK3</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the MAPK3 gene.

<span class="mw-page-title-main">MAP2K1</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MAP2K1 gene.

<span class="mw-page-title-main">MAP2K2</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">ELK1</span> Protein-coding gene in humans

ETS Like-1 protein Elk-1 is a protein that in humans is encoded by the ELK1. Elk-1 functions as a transcription activator. It is classified as a ternary complex factor (TCF), a subclass of the ETS family, which is characterized by a common protein domain that regulates DNA binding to target sequences. Elk1 plays important roles in various contexts, including long-term memory formation, drug addiction, Alzheimer's disease, Down syndrome, breast cancer, and depression.

<span class="mw-page-title-main">RPS6KA1</span> Enzyme

Ribosomal protein S6 kinase alpha-1 is an enzyme that in humans is encoded by the RPS6KA1 gene.

<span class="mw-page-title-main">RPS6KA2</span> Enzyme found in humans

Ribosomal protein S6 kinase alpha-2 is an enzyme that in humans is encoded by the RPS6KA2 gene.

<span class="mw-page-title-main">DUSP6</span> Protein-coding gene in humans

Dual specificity phosphatase 6 (DUSP6) is an enzyme that in humans is encoded by the DUSP6 gene.

<span class="mw-page-title-main">PTPRR</span> Protein-coding gene in the species Homo sapiens

Protein tyrosine phosphatase receptor-type R is an enzyme that in humans is encoded by the PTPRR gene.

<span class="mw-page-title-main">DUSP3</span> Protein-coding gene in the species Homo sapiens

Dual specificity protein phosphatase 3 is an enzyme that in humans is encoded by the DUSP3 gene.

<span class="mw-page-title-main">MAPK6</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 6 is an enzyme that in humans is encoded by the MAPK6 gene.

<span class="mw-page-title-main">DUSP4</span> Protein-coding gene in the species Homo sapiens

Dual specificity protein phosphatase 4 is an enzyme that in humans is encoded by the DUSP4 gene.

<span class="mw-page-title-main">MAPK phosphatase</span>

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 regulation, cell proliferation, programmed cell death and stress responses. MAPK phosphatases are therefore important regulator components of these pathways.

Candidalysin is a cytolytic 31-amino acid α-helical amphipathic peptide toxin secreted by the opportunistic pathogen Candida albicans. This toxin is a fungal example of a classical virulence factor. Hyphal morphogenesis in C. albicans is associated with damage to host epithelial cells; during this process Candidalysin is released and intercalates in host membranes. Candidalysin promotes damage of oral epithelial cells and induces lactate dehydrogenase release and calcium ion influx. It is unique in the fact that it is the first peptide toxin to be identified in any human fungal pathogen.

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. 1 2 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.