MAPK15
Mitogen-activated protein kinase 15, also known as MAPK15, ERK7, or ERK8, is an enzyme that in humans is encoded by the MAPK15 gene.[5][6]
Evolutionarily, MAPK15 is conserved in a number of species, including P. troglodytes, B. taurus, M. musculus, R. norvegicus, D. rerio, D. melanogaster, C. elegans, and X. laevis.[6]
Function
The protein encoded by this gene is a member of the MAP (mitogen-activated protein) kinase family. MAP kinases are also known as extracellular signal-regulated kinases (ERKs), and are involved in signaling cascades that regulate a number of cellular processes, including proliferation, differentiation, and transcriptional regulation. MAPK15 is often referred to as ERK7 or ERK8, and the latter two share 69% amino acid sequence similarity; at least one study has suggested that the two are, in fact, distinct proteins.
In vertebrate models, ERK8 is not constitutively active, and exhibits relatively low basal kinase activity.[7] It contains two SH3 (SRC homology 3) binding motifs in its C-terminal region, and is likely activated by an SRC-dependent signaling pathway.[5] SRC is a non-receptor tyrosine kinase (and proto-oncogene) that has been implicated in cancer growth and progression in humans when it is overexpressed. The exact function of MAPK15 is unknown, though a number of studies have implicated the enzyme in various cellular pathways.
Specifically, MAPK15 expression is significantly reduced in human lung and breast carcinomas, and MAPK15 down-regulation is correlated with increased cell motility.[7] MAPK15 has also been found to negatively regulate protein O-glycosylation with acetyl galactosamine (GalNAc), a process in which a sugar molecule is covalently attached to an oxygen atom on an amino acid residue.[7] Mammalian MAPK15 is a putative regulator of the cellular localization and transcriptional activity of estrogen-related receptor alpha (ERRa), as well as an inhibitor of proliferating cell nuclear antigen (PCNA) degradation.[8][9] PCNA is critical for DNA replication, and is an essential factor in protecting genome stability. MAPK15 has also been shown to regulate ciliogenesis in X. laevis (African clawed frog) embryos by phosphorylating an actin regulator called CapZIP.[10]
Interactions
MAPK15 has been demonstrated to interact with gamma-aminobutyric acid receptor-associated protein (GABARAP) and microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A, or LC3) in a process that stimulates autophagy.[11] A number of additional proteins also interact with MAPK15, including cyclin-dependent kinase 2 (CDK2), mitogen-activated protein kinase 12 (MAPK12), and lactotransferrin (LTF), among many others.[6]
Clinical significance
Due to its role in protecting genomic integrity and cell motility, MAPK15 has been identified as a potential target for cancer therapeutics.[12] Additionally, given the putative role that MAPK15 plays in the regulation of ciliogenesis, it may be an ideal target for diseases related to human ciliary defects (often called ciliopathies).
References
- 1 2 3 ENSG00000274205 GRCh38: Ensembl release 89: ENSG00000181085, ENSG00000274205 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000063704 - Ensembl, May 2017
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- 1 2 Abe MK, Saelzler MP, Espinosa R, Kahle KT, Hershenson MB, Le Beau MM, Rosner MR (May 2002). "ERK8, a new member of the mitogen-activated protein kinase family". The Journal of Biological Chemistry. 277 (19): 16733–43. PMID 11875070. doi:10.1074/jbc.M112483200.
- 1 2 3 "Entrez Gene: MAPK15 mitogen-activated protein kinase 15".
- 1 2 3 Chia J, Tham KM, Gill DJ, Bard-Chapeau EA, Bard FA (2014). "ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration". eLife. 3: e01828. PMC 3945522
. PMID 24618899. doi:10.7554/eLife.01828. - ↑ Rossi M, Colecchia D, Iavarone C, Strambi A, Piccioni F, Verrotti di Pianella A, Chiariello M (Mar 2011). "Extracellular signal-regulated kinase 8 (ERK8) controls estrogen-related receptor α (ERRα) cellular localization and inhibits its transcriptional activity". The Journal of Biological Chemistry. 286 (10): 8507–22. PMC 3048734 . PMID 21190936. doi:10.1074/jbc.M110.179523.
- ↑ Groehler AL, Lannigan DA (Aug 2010). "A chromatin-bound kinase, ERK8, protects genomic integrity by inhibiting HDM2-mediated degradation of the DNA clamp PCNA". The Journal of Cell Biology. 190 (4): 575–86. PMC 2928013 . PMID 20733054. doi:10.1083/jcb.201002124.
- ↑ Miyatake K, Kusakabe M, Takahashi C, Nishida E (2015). "ERK7 regulates ciliogenesis by phosphorylating the actin regulator CapZIP in cooperation with Dishevelled". Nature Communications. 6: 6666. PMID 25823377. doi:10.1038/ncomms7666.
- ↑ Colecchia D, Strambi A, Sanzone S, Iavarone C, Rossi M, Dall'Armi C, Piccioni F, Verrotti di Pianella A, Chiariello M (Dec 2012). "MAPK15/ERK8 stimulates autophagy by interacting with LC3 and GABARAP proteins". Autophagy. 8 (12): 1724–40. PMC 3541284 . PMID 22948227. doi:10.4161/auto.21857.
- ↑ Strambi A, Mori M, Rossi M, Colecchia D, Manetti F, Carlomagno F, Botta M, Chiariello M (2013). "Structure prediction and validation of the ERK8 kinase domain". PLOS ONE. 8 (1): e52011. PMC 3543423 . PMID 23326322. doi:10.1371/journal.pone.0052011.
Further reading
- Saelzler MP, Spackman CC, Liu Y, Martinez LC, Harris JP, Abe MK (Jun 2006). "ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5". The Journal of Biological Chemistry. 281 (24): 16821–32. PMID 16624805. doi:10.1074/jbc.M512418200.
- Iavarone C, Acunzo M, Carlomagno F, Catania A, Melillo RM, Carlomagno SM, Santoro M, Chiariello M (Apr 2006). "Activation of the Erk8 mitogen-activated protein (MAP) kinase by RET/PTC3, a constitutively active form of the RET proto-oncogene". The Journal of Biological Chemistry. 281 (15): 10567–76. PMID 16484222. doi:10.1074/jbc.M513397200.
- Klevernic IV, Stafford MJ, Morrice N, Peggie M, Morton S, Cohen P (Feb 2006). "Characterization of the reversible phosphorylation and activation of ERK8". The Biochemical Journal. 394 (Pt 1): 365–73. PMC 1386035 . PMID 16336213. doi:10.1042/BJ20051288.
- Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S (Sep 2004). "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions". Genome Research. 14 (9): 1711–8. PMC 515316 . PMID 15342556. doi:10.1101/gr.2435604.
- Kinet S, Bernard F, Mongellaz C, Perreau M, Goldman FD, Taylor N (Oct 2002). "gp120-mediated induction of the MAPK cascade is dependent on the activation state of CD4(+) lymphocytes". Blood. 100 (7): 2546–53. PMID 12239168. doi:10.1182/blood-2002-03-0819.
- Qian Z, Okuhara D, Abe MK, Rosner MR (Jan 1999). "Molecular cloning and characterization of a mitogen-activated protein kinase-associated intracellular chloride channel". The Journal of Biological Chemistry. 274 (3): 1621–7. PMID 9880541. doi:10.1074/jbc.274.3.1621.