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{{main|Mitogen-activated protein kinase}}
In [[molecular biology]], '''extracellular signal–regulated kinases''' ('''ERKs''') or '''classical MAP kinases''' are widely expressed [[protein kinase]] [[cell signalling|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  [[Guanine Nucleotide-Binding Protein-Coupled Receptor|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 [[mammal]]ian MAPK family.{{citation needed|date=May 2016}}


In the [[MAPK/ERK pathway]], [[Ras (protein)|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 [[growth factor receptor-bound protein 2|GRB2]]/[[son of sevenless|SOS]], but may also receive other signals.  ERKs are known to activate many [[transcription factors]], such as [[ELK1]],<ref name="pmid8208531">{{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 }}</ref> and some downstream protein kinases.


In [[molecular biology]], '''extracellular signal-regulated kinases''' (ERKs) or '''classical MAP kinases''' are widely expressed [[protein kinase]] [[cell signalling|intracellular signalling]] molecules which 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 [[Guanine Nucleotide-Binding Protein-Coupled Receptor|G protein-coupled receptors]], transforming agents, and [[carcinogens]], activate the ERK pathway.{{Fact|date=February 2007}}
Disruption of the ERK pathway is common in cancers, especially Ras, c-Raf and receptors such as [[HER2]].


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 [[mammal]]ian MAPK family. In the [[MAPK/ERK pathway]], [[Ras]] activates [[c-Raf]], followed by [[MEK]] and then MAPK1/2 (below).  Ras is typically activated by growth hormones through [[receptor tyrosine kinases]] and [[growth factor receptor-bound protein 2|GRB2]]/[[son of sevenless|SOS]], but may also receive other signals.  ERKs are known to activate many transcription factors 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}}
{{infobox protein | Name = '''[[MAPK1|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 = }}
[[MAPK1|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.<ref name="Boulton1991">{{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 }}</ref> They were found during a search for protein kinases that are rapidly [[phosphorylated]] after activation of cell surface [[tyrosine kinase]]s such as the [[epidermal growth factor receptor]]. Phosphorylation of ERKs leads to the activation of their kinase activity.


==Mitogen-activated protein kinase 1==
The molecular events linking cell surface receptors to activation of ERKs are complex. It was found that [[Ras (protein)|Ras]] GTP-binding proteins are involved in the activation of ERKs.<ref name="Leevers1992">{{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 }}</ref> Another protein kinase, [[c-Raf|Raf-1]], was shown to phosphorylate a "MAP kinase-kinase", thus qualifying as a "MAP kinase kinase kinase".<ref name="Kyriakis1992">{{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 }}</ref> The MAP kinase-kinase, which activates ERK, was named "'''M'''APK/'''E'''RK '''k'''inase" ('''[[Mitogen-activated protein kinase kinase|MEK]]''').<ref name="Crews1992">{{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 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1381507 }}</ref>
{{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 (85% sequence identity) protein kinases were originally called ERK1 and ERK2.<ref name="Boulton1991">T. G. Boulton and M. H. Cobb (1991) "Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies" in ''Cell Regulation'' Volume 2, pages 357-571. {{Entrez Pubmed|1654126}}.</ref> They were found during a search for protein kinases that are rapidly phosphorylated after activation of cell surface [[tyrosine kinase]]s 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.<ref name="Leevers1992">S. J. Leevers and C. J. Marshall (1992) "Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein" in ''[[EMBO Journal|The EMBO Journal]]'' Volume 11, page 569-574. {{Entrez Pubmed|1371463}}.</ref> Another protein kinase, [[c-Raf|Raf-1]], was shown to phosphorylate a "MAPK kinase", thus qualifying as a "MAPK kinase kinase".<ref name="Kyriakis1992">J. M. Kyriakis, H. App, X. F. Zhang, P. Banerjee, D. L. Brautigan, U. R. Rapp and J. Avruch (1992) "Raf-1 activates MAP kinase-kinase" in ''[[Nature (journal)|Nature]] Volume 358, pages 417-421.{{Entrez Pubmed|1322500}}.</ref> The MAPK kinase was named "'''M'''APK/'''E'''RK '''k'''inase" ('''MEK''').<ref name="Crews1992"> C. M. Crews and R. L. Erikson (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" in ''[[Proceedings of the National Academy of Sciences|Proceedings of the National Academy of Sciences of the United States of America]]'' Volume 89, pages 8205-8209. {{Entrez Pubmed|1381507}}.</ref>
Receptor-linked [[tyrosine kinases]], [[Ras subfamily|Ras]], [[Raf kinase|Raf]], [[Mitogen-activated protein kinase kinase|MEK]], and [[MAPK]] could be fitted into a signaling cascade linking an extracellular signal to MAPK activation.<ref name="Itoh1993">{{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 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8381539 }}</ref> See: [[MAPK/ERK pathway]].


Receptor-linked tyrosine kinases, Ras, Raf, MEK and MAPK could be fitted into a signaling cascade linking an extracellular signal to MAPK activation.<ref name="Itoh1993">T. Itoh, K. Kaibuchi, T. Masuda, T. Yamamoto, Y. Matsuura, A. Maeda, K. Shimizu and Y. Takai (1993) "A protein factor for ras p21-dependent activation of mitogen-activated protein (MAP) kinase through MAP kinase kinase" in
Transgenic [[gene knockout]] mice lacking MAPK1 have major defects in early development.<ref name="Yao2003">{{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 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=14566055 }}</ref> 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.<ref name="pmid27486885">{{cite journal | vauthors = Peroumal D, Abimannan T, Tagirasa R, Parida JR, Singh SK, Padhan P, Devadas S | title = Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance | journal = Oncotarget | volume =  | issue =  | date = July 2016 | pmid = 27486885 | doi = 10.18632/oncotarget.10913 }}</ref>
''[[Proceedings of the National Academy of Sciences|Proceedings of the National Academy of Sciences of the United States of America]]'' Volume 90, pages 975-979. {{Entrez Pubmed|8381539}}.</ref> See: [[MAPK/ERK pathway]].


Transgenic [[gene knockout]] mice lacking MAPK1 have major defects in early development.<ref name="Yao2003">Y. Yao W. Li, J. Wu, U. A. Germann, M. S. Su, K. Kuida and D. M. Boucher (2003) "Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation" in  
== Mitogen-activated protein kinase 3 ==
''[[Proceedings of the National Academy of Sciences|Proceedings of the National Academy of Sciences of the United States of America]]'' Volume 100, pages 12759-12764. {{Entrez Pubmed|14566055}}.</ref>
{{see also|MAPK3}}
{{infobox protein | Name = '''[[MAPK3|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 = }}
[[MAPK3|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.<ref name="Pages1999">{{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 | url = http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=10558995 }}</ref> The main exception is in [[T cell]]s. Mice lacking [[MAPK3]] have  reduced T cell development past the CD4<sup>+</sup>CD8<sup>+</sup> stage.


==Mitogen-activated protein kinase 3==  
== References ==
{{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 = }}
{{Reflist|33em}}
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.<ref name="Pages1999"> G. Pages, S. Guerin, D. Grall, F. Bonino, A. Smith, F. Anjuere P. Auberger and J. Pouyssegur (1999) "Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice" in ''[[Science (journal)|Science]] Volume 286, pages 1374-1377.
{{Entrez Pubmed|10558995}}.</ref> The main exception is in [[T cell]]s. Mice lacking MAPK3 have  reduced T cell development past the CD4<sup>+</sup>CD8<sup>+</sup> stage.


==External links==
== External links ==
* [http://macromoleculeinsights.com/erk.php The Extracellular Signal-Regulated Kinases]
* [http://www.mapkinases.eu MAP Kinase Resource ].
* {{MeshName|Extracellular+Signal-Regulated+MAP+Kinases}}
* {{MeshName|Extracellular+Signal-Regulated+MAP+Kinases}}
 
* [http://cmkb.cellmigration.org/report.cgi?report=orth_overview&gene_id=5594 MAPK1]
==References==
* [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]
 
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Revision as of 22:39, 21 September 2018

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
SymbolMAPK1
Alt. symbolsPRKM2, PRKM1
Entrez5594
HUGO6871
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
Entrez5595
HUGO6877
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.

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. 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. doi:10.18632/oncotarget.10913. 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.

External links

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