MAPK15 explained

Mitogen-activated protein kinase 15, also known as MAPK15, ERK7, or ERK8, is an enzyme that in humans is encoded by the MAPK15 gene.^{[1] [2]}

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.^[2]

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.^[3] It contains two SH3 (SRC homology 3) binding motifs in its C-terminal region, and is likely activated by an SRC-dependent signaling pathway.^[1] 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.^{[4] [5]} 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.^[6]

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.^[7] 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.^[2]

Clinical significance

Due to its role in protecting genomic integrity and cell motility, MAPK15 has been identified as a potential target for cancer therapeutics.^[8] 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).

Further reading

• Saelzler MP, Spackman CC, Liu Y, Martinez LC, Harris JP, Abe MK . ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5 . The Journal of Biological Chemistry . 281 . 24 . 16821–32 . Jun 2006 . 16624805 . 10.1074/jbc.M512418200 . free .
• Iavarone C, Acunzo M, Carlomagno F, Catania A, Melillo RM, Carlomagno SM, Santoro M, Chiariello M . 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 . Apr 2006 . 16484222 . 10.1074/jbc.M513397200 . 45690153 . free .
• Klevernic IV, Stafford MJ, Morrice N, Peggie M, Morton S, Cohen P . Characterization of the reversible phosphorylation and activation of ERK8 . The Biochemical Journal . 394 . Pt 1 . 365–73 . Feb 2006 . 16336213 . 1386035 . 10.1042/BJ20051288 .
• Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S . Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions . Genome Research . 14 . 9 . 1711–8 . Sep 2004 . 15342556 . 515316 . 10.1101/gr.2435604 .
• Kinet S, Bernard F, Mongellaz C, Perreau M, Goldman FD, Taylor N . gp120-mediated induction of the MAPK cascade is dependent on the activation state of CD4(+) lymphocytes . Blood . 100 . 7 . 2546–53 . Oct 2002 . 12239168 . 10.1182/blood-2002-03-0819 . free .
• Qian Z, Okuhara D, Abe MK, Rosner MR . Molecular cloning and characterization of a mitogen-activated protein kinase-associated intracellular chloride channel . The Journal of Biological Chemistry . 274 . 3 . 1621–7 . Jan 1999 . 9880541 . 10.1074/jbc.274.3.1621 . free .

External links

• MAP Kinase Resource

Notes and References

1. Abe MK, Saelzler MP, Espinosa R, Kahle KT, Hershenson MB, Le Beau MM, Rosner MR . ERK8, a new member of the mitogen-activated protein kinase family . The Journal of Biological Chemistry . 277 . 19 . 16733–43 . May 2002 . 11875070 . 10.1074/jbc.M112483200 . free .
2. Web site: Entrez Gene: MAPK15 mitogen-activated protein kinase 15.
3. Chia J, Tham KM, Gill DJ, Bard-Chapeau EA, Bard FA . ERK8 is a negative regulator of O-GalNAc glycosylation and cell migration . eLife . 3 . e01828 . 2014 . 24618899 . 10.7554/eLife.01828 . 3 . 3945522 . free .
4. Rossi M, Colecchia D, Iavarone C, Strambi A, Piccioni F, Verrotti di Pianella A, Chiariello M . 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 . Mar 2011 . 21190936 . 10.1074/jbc.M110.179523 . 3048734. free .
5. Groehler AL, Lannigan DA . 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 . Aug 2010 . 20733054 . 10.1083/jcb.201002124 . 2928013.
6. Miyatake K, Kusakabe M, Takahashi C, Nishida E . ERK7 regulates ciliogenesis by phosphorylating the actin regulator CapZIP in cooperation with Dishevelled . Nature Communications . 6 . 6666 . 25823377 . 10.1038/ncomms7666 . 2015. 2015NatCo...6.6666M . free .
7. Colecchia D, Strambi A, Sanzone S, Iavarone C, Rossi M, Dall'Armi C, Piccioni F, Verrotti di Pianella A, Chiariello M . MAPK15/ERK8 stimulates autophagy by interacting with LC3 and GABARAP proteins . Autophagy . 8 . 12 . 1724–40 . Dec 2012 . 22948227 . 10.4161/auto.21857 . 3541284.
8. Strambi A, Mori M, Rossi M, Colecchia D, Manetti F, Carlomagno F, Botta M, Chiariello M . Structure prediction and validation of the ERK8 kinase domain . PLOS ONE . 8 . 1 . e52011 . 23326322 . 10.1371/journal.pone.0052011 . 3543423 . 2013. 2013PLoSO...852011S . free .