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. It contains two SH3 (SRC homology 3) binding motifs in its C-terminal region, and is likely activated by an SRC-dependent signaling pathway. 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. 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. 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. 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.
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. 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.
Due to its role in protecting genomic integrity and cell motility, MAPK15 has been identified as a potential target for cancer therapeutics. 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).
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^ abcChia 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. doi:10.7554/eLife.01828. PMID24618899.
^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. doi:10.1074/jbc.M110.179523. PMID21190936.
^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. doi:10.1083/jcb.201002124. PMID20733054.
^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. doi:10.1038/ncomms7666. PMID25823377.
^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. doi:10.4161/auto.21857. PMID22948227.
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. doi:10.1074/jbc.M512418200. PMID16624805.
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