MAPK6

MAPK6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2I6L
Identifiers
Aliases	MAPK6 , ERK3, HsT17250, PRKM6, p97MAPK, mitogen-activated protein kinase 6
External IDs	OMIM: 602904; MGI: 1354946; HomoloGene: 55683; GeneCards: MAPK6; OMA:MAPK6 - orthologs
Gene location (Human) Chr. Chromosome 15 (human) [1] Band 15q21.2 Start 51,952,106 bp [1] End 52,067,375 bp [1]
Gene location (Mouse) Chr. Chromosome 9 (mouse) [2] Band 9 D|9 42.3 cM Start 75,276,344 bp [2] End 75,317,287 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cartilage tissue gums gingival epithelium mucosa of ileum hair follicle cervix epithelium middle temporal gyrus pons skin of thigh body of tongue Top expressed in spermatocyte spermatid seminiferous tubule zygote ganglionic eminence somite molar mandibular prominence medial ganglionic eminence maxillary prominence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function kinase activity transferase activity nucleotide binding protein serine/threonine kinase activity protein kinase activity protein binding ATP binding protein kinase binding protein heterodimerization activity MAP kinase activity Cellular component nucleoplasm septin cytoskeleton cytosol nucleus cytoplasm protein-containing complex Biological process protein phosphorylation cell cycle phosphorylation signal transduction MAPK cascade positive regulation of dendritic spine development regulation of gene expression cellular response to organic substance intracellular signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5597 50772 Ensembl ENSG00000069956 ENSMUSG00000042688 UniProt Q16659 Q61532 RefSeq (mRNA) NM_002748 NM_015806 NM_027418 RefSeq (protein) NP_002739 NP_056621 NP_081694 Location (UCSC) Chr 15: 51.95 – 52.07 Mb Chr 9: 75.28 – 75.32 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Mitogen-activated protein kinase 6 is an enzyme that in humans is encoded by the MAPK6 gene. ^{[5] [6]}

The protein encoded by this gene is a member of the Ser/Thr protein kinase family, and is most closely related to mitogen-activated protein kinases (MAP kinases). MAP kinases, also known as extracellular signal-regulated kinases (ERKs), are activated through protein phosphorylation cascades and act as integration points for multiple biochemical signals. This kinase is localized in the nucleus, and has been reported to be activated in fibroblasts upon treatment with serum or phorbol esters. ^[6]

Discovery

ERK3/MAPK6 was initially cloned from the rat brain cDNA library by homology screening with probes ERK1 derived probe. ^[7]

Gene location

In humans, MAPK 6 gene  is located on the distal arm of chromosome 15 (15q21.2). It is 47.01kb long and is transcribed in the centromere to telomere orientation. It consist of 6 exons with the translation initiation codon which is located in exon2. ^[8]

Structure

It is an atypical member of the mitogen activated kinases family. The molecular mass of the translated protein is approximately 100kDa, and is made up of 721 amino acid residues. ^{[8] [7]} It contains a typical kinase domain at the N- terminal and an extended C- terminal. The first 150 residues at c- terminal are 50% similar to ERK4 protein. At the kinase domain it exhibits about 70% similarity with the ERK4 protein. ^{[8] [7]} The activation loop of the phosphorylation motif contains only one phospho acceptor site (Ser-Glu-Gly). ^[7]

The structure is predicted by homology modelling using the crystal structure of phoshphorylated ERK2. According to the model, the structure of ERK3/MAPK6 kinase domain resembles other MAP kinases. The modelled ERK3/MAPK6 kinase domain is predicted to fold with a topology similar to other MAP kinases. ^[7]

Expression

ERK3/MAPK6 is widely expressed protein however it is expressed in significantly higher amounts in skeletal muscles and brain. It is localized in cytoplasm and the nucleus of cells. ERK3/MAPK6 is a highly unstable protein and has a very little half life of less than an hour. It is degraded by ubiquitin mediated proteasomal pathway. ^[8]

Function

It is very important for neonatal growth and survival. ERK3/MAPK6 forms a complex with microtubule associated protein2 (MAP2) and MAPKAPK5 which mediates the phosphorylation of MAPKAPK5 which in turn phosphorylates ERK3/MAPK6 at serine 189 residue mediating the entry into cell cycle. ^[9] It also acts as a regulator for T- cell development. The catalytic activity of ERK3/MAPK6 plays an important for the proper differentiation of T-cells in the thymus. The long c- terminal is responsible for thymic differentiation. ^[10]

Role in cancer

ERK3/MAPK6 interacts with and phosphorylated steroid receptor coactivator 3 (SRC-3) This coreceptor is an oncogenic protein which when overexpressed at serine 857 leads to cancer. After the phosphorylation of SRC-3 results in the upregulation of MMP activity ERK3-mediated phosphorylation at S857 was essential for interaction of SRC-3 with the ETS transcription factor PEA3, which promotes upregulation of MMP gene expression and proinvasive activity. ^[11]

References

1. GRCh38: Ensembl release 89: ENSG00000069956 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000042688 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Meloche S (2005-04-01). "Erk3". AfCS-Nature Molecule Pages. doi:10.1038/mp.a000876.01 (inactive 1 November 2024). ISSN   1477-5921.
6. "MAPK6 mitogen-activated protein kinase 6 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-11-09.
7. Coulombe P, Meloche S (August 2007). "Atypical mitogen-activated protein kinases: structure, regulation and functions". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1773 (8): 1376–87. doi: 10.1016/j.bbamcr.2006.11.001 . PMID   17161475.
8. "MAPK6 (mitogen-activated protein kinase 6)". atlasgeneticsoncology.org. Retrieved 2018-11-09.
9. "Volume II Accession Number Index", Rodents, Elsevier, 1987, pp. ACCESSION–1–ACCESSION–5, doi:10.1016/b978-0-12-512512-3.50015-8, ISBN   978-0-12-512512-3
10. Marquis M, Daudelin JF, Boulet S, Sirois J, Crain K, Mathien S, Turgeon B, Rousseau J, Meloche S, Labrecque N (September 2014). "The catalytic activity of the mitogen-activated protein kinase extracellular signal-regulated kinase 3 is required to sustain CD4+ CD8+ thymocyte survival". Molecular and Cellular Biology. 34 (18): 3374–87. doi:10.1128/MCB.01701-13. PMC   4135614 . PMID   25002529.
11. Long W, Foulds CE, Qin J, Liu J, Ding C, Lonard DM, Solis LM, Wistuba II, Qin J, Tsai SY, Tsai MJ, O'Malley BW (May 2012). "ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion". The Journal of Clinical Investigation. 122 (5): 1869–80. doi:10.1172/jci61492. PMC   3336992 . PMID   22505454.

Further reading

• Boulton TG, Nye SH, Robbins DJ, Ip NY, Radziejewska E, Morgenbesser SD, DePinho RA, Panayotatos N, Cobb MH, Yancopoulos GD (May 1991). "ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF". Cell. 65 (4): 663–75. doi:10.1016/0092-8674(91)90098-J. PMID   2032290. S2CID   35051321.
• Zhu AX, Zhao Y, Moller DE, Flier JS (December 1994). "Cloning and characterization of p97MAPK, a novel human homolog of rat ERK-3". Molecular and Cellular Biology. 14 (12): 8202–11. doi:10.1128/MCB.14.12.8202. PMC   359359 . PMID   7969157.
• Cheng M, Boulton TG, Cobb MH (April 1996). "ERK3 is a constitutively nuclear protein kinase". The Journal of Biological Chemistry. 271 (15): 8951–8. doi: 10.1074/jbc.271.15.8951 . PMID   8621539.
• Sauma S, Friedman E (May 1996). "Increased expression of protein kinase C beta activates ERK3". The Journal of Biological Chemistry. 271 (19): 11422–6. doi: 10.1074/jbc.271.19.11422 . PMID   8626698.
• Zimmermann J, Lamerant N, Grossenbacher R, Furst P (April 2001). "Proteasome- and p38-dependent regulation of ERK3 expression". The Journal of Biological Chemistry. 276 (14): 10759–66. doi: 10.1074/jbc.M008567200 . PMID   11148204.
• Robinson MJ, Xu Be BE, Stippec S, Cobb MH (February 2002). "Different domains of the mitogen-activated protein kinases ERK3 and ERK2 direct subcellular localization and upstream specificity in vivo". The Journal of Biological Chemistry. 277 (7): 5094–100. doi: 10.1074/jbc.M110935200 . PMID   11741894.
• Kinet S, Bernard F, Mongellaz C, Perreau M, Goldman FD, Taylor N (October 2002). "gp120-mediated induction of the MAPK cascade is dependent on the activation state of CD4(+) lymphocytes". Blood. 100 (7): 2546–53. doi: 10.1182/blood-2002-03-0819 . PMID   12239168.
• Coulombe P, Rodier G, Pelletier S, Pellerin J, Meloche S (July 2003). "Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation". Molecular and Cellular Biology. 23 (13): 4542–58. doi:10.1128/MCB.23.13.4542-4558.2003. PMC   164847 . PMID   12808096.
• Julien C, Coulombe P, Meloche S (October 2003). "Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression". The Journal of Biological Chemistry. 278 (43): 42615–24. doi: 10.1074/jbc.M302724200 . PMID   12915405.
• Rai R, Mahale A, Saranath D (August 2004). "Molecular cloning, isolation and characterisation of ERK3 gene from chewing-tobacco induced oral squamous cell carcinoma". Oral Oncology. 40 (7): 705–12. doi:10.1016/j.oraloncology.2004.01.010. PMID   15172640.
• Coulombe P, Rodier G, Bonneil E, Thibault P, Meloche S (July 2004). "N-Terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasome". Molecular and Cellular Biology. 24 (14): 6140–50. doi:10.1128/MCB.24.14.6140-6150.2004. PMC   434260 . PMID   15226418.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID   16189514. S2CID   4427026.
• Hoeflich KP, Eby MT, Forrest WF, Gray DC, Tien JY, Stern HM, Murray LJ, Davis DP, Modrusan Z, Seshagiri S (October 2006). "Regulation of ERK3/MAPK6 expression by BRAF". International Journal of Oncology. 29 (4): 839–49. doi: 10.3892/ijo.29.4.839 . PMID   16964379.

External links

• MAP Kinase Resource Archived 2021-04-15 at the Wayback Machine .