MAPK6

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Mitogen-activated protein kinase 6 is an enzyme that in humans is encoded by the MAPK6 gene.[1][2]

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.[2]

Discovery

ERK3/MAPK6 was initially cloned from the rat brain cDNA library by homology screening with probes ERK1 derived probe.[3]

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.[4]

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.[4][3] 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.[4][3] The activation loop of the phosphorylation motif contains only one phospho acceptor site (Ser-Glu-Gly).[3]

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.[3]

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.[4]

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.[5] 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.[6]

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.[7]

References

  1. Meloche, Sylvain (2005-04-01). "Erk3". AfCS-Nature Molecule Pages. doi:10.1038/mp.a000876.01. ISSN 1477-5921.
  2. 2.0 2.1 "MAPK6 mitogen-activated protein kinase 6 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-11-09.
  3. 3.0 3.1 3.2 3.3 3.4 Coulombe P, Meloche S (August 2007). "Atypical mitogen-activated protein kinases: structure, regulation and functions". Biochimica et Biophysica Acta. 1773 (8): 1376–87. doi:10.1016/j.bbamcr.2006.11.001. PMID 17161475.
  4. 4.0 4.1 4.2 4.3 "MAPK6 (mitogen-activated protein kinase 6)". atlasgeneticsoncology.org. Retrieved 2018-11-09.
  5. "Volume II Accession Number Index", Rodents, Elsevier, pp. ACCESSION–1-ACCESSION-5, 1987, ISBN 9780125125123, retrieved 2018-11-09
  6. 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.
  7. 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

External links


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