Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review MAPK7 (mitogen-activated protein kinase 7) Francisco de Asís Iñesta-Vaquera, Ana Cuenda Centro Nacional de Biotecnologia-CSIC, Department of Immunology and Oncology, Madrid, Spain (FdAIV, AC) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK7ID41294ch17p11.html DOI: 10.4267/2042/44909 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology (MAPK7a, b and c) have been reported. Mouse splice variants are generated by alternative splicing across introns 1 and/or 2 (Yan et al., 2001). Identity Other names: BMK1, ERK4, ERK5, PRKM7 HGNC (Hugo): MAPK7 Location: 17p11.2 Pseudogene DNA/RNA Protein Description Note ERK5, also known as MAPK7 or "Big MAP-Kinase 1" (BMK1) belongs to the Mitogen Activated Protein Kinase (MAPK) family, and therefore to the CGMC kinases in the human kinome (Manning et al., 2002). ERK5, at 98 kDa, is twice the size of other MAPKs and hence the largest kinase within its group. No human or mouse pseudogene known. The MAPK7 entire gene spans 5,82 kb on the short arm of chromosome 17. It contains 6 exons. Transcription The human MAPK7 gene encodes an 816 amino-acids protein of about 98 kDa. MAPK7 mRNA is 2445 bp. There are 11 transcripts, seven of which are protein coding. In mice, three splice variants MAPK7 genomic context (Chromosome 17; location 17p11.2). Genomic organization of MAPK7 gene on chromosome 17p11.2. The boxes indicate coding regions (exons 1-6) of the gene. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1111 MAPK7 (mitogen-activated protein kinase 7) Iñesta-Vaquera FdA, Cuenda A Schematic representation of the human ERK5 (MAPK7) protein domains. NES1 and NES2, bipartite nuclear exportation signal; PB1-BD, PB1 (Phox and Bem domain 1) binding domain; Kinase Domain, catalytic kinase domain; TEY, sequence motif containing ERK5 regulatory phosphorylation residues; PR-1 and PR-2, proline rich domains; Transcriptional trans-activation, transcriptional activity domain. It possesses a catalytic N-terminal domain, which share 50% homology with ERK1 (MAPK3) and ERK2 (MAPK1) and a unique C-terminal tail of about 400 amino-acids long. In vivo, ERK5 is activated to the same extent by environmental stresses, such as oxidative and osmotic shock, and by growth factors. In addition, ERK5 may be activated by the cytokine Interleukin-6 in B cells. Function Genetic studies have shown that ERK5 (MAPK7) is essential for cardiovascular development and neuronal differentiation. ERK5 knock-out mice die at midgestation due to developmental failures in structures as placenta, heart and vascular system (Regan et al., 2002; Sohn et al., 2002; Yan et al., 2003; Hayashi et al., 2004; Wang et al., 2005). ERK5 also regulates cell survival in a variety of tissues. At nervous system, ERK5 acts as a neuroprotector from neurotrophic factor withdrawal and toxic insults (Cavanaugh, 2004). Also, ERK5 is required to mediate the survival response of neurons to nerve growth factor (Finegan et al., 2009). In the immune system, the ERK5 pathway regulates apoptosis of developing thymocytes (Sohn et al., 2008) and protects B cells from proapoptotic stimuli (Carvajal-Vergara et al., 2005). ERK5 is also required for cell cycle progression. It regulates cyclin D1 expression (Mulloy et al., 2003) and is necessary for EGF-induced cell proliferation and progression through the cell cycle (Kato et al., 1998). Moreover, it has been suggested that the ERK5NFKappaB pathway may be required for a timely mitotic entry (Cude et al., 2007). Additionally, ERK5, along with other MAPK pathways can play an indirect role in cytoskeleton rearrangement (Barros and Marshall, 2005), in promoting SRC-induced podosome formation (Schramp et al., 2008), and in cell attachment to the extracellular matrix and in endothelial cell migration (Spiering et al., 2009; Sawhney et al., 2009). ERK5 (MAPK7) is a protein with kinase activity (in its N-terminal region) and also transcriptional activation activity (in the C-terminal half). Downstream targets of ERK5 include the transcription factors MEF2A, Description Human ERK5 (MAPK7) is a Ser/Thr protein kinase of 816 amino-acids with a predicted mass of 98 kDa. The ERK5 N-terminus domain resembles the typical MAPK catalytic domain and includes the MAPK-conserved TXY activation sequence (T218EY220) in the activation loop. The activation of ERK5 occurs via interaction with and dual phosphorylation in its TEY motif by MKK5 (Mody et al., 2003). MKK5 mediated ERK5 activation leads to ERK5 autophosphorylation in its unique C-terminal domain (Morimoto et al., 2007). Expression ERK5 (MAPK7) mRNA throughout all tissues. is widely expressed Localisation Both in tissues and in cultured cells, ERK5 (MAPK7) localizes to the cytoplasm of cells and/or to the nucleus. As shown in the above diagram, ERK5 molecule contains a bipartite nuclear exportation signal. In resting cells, the N- and C-terminal halves of ERK5 interact producing a nuclear export signal (NES) that retains ERK5 in the cytoplasm of the cells. Upon stimulation, the interaction between the N- and the Cterminal halves is disrupted, and therefore ERK5 enters the nucleus (Kondoh et al., 2006). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1112 MAPK7 (mitogen-activated protein kinase 7) Iñesta-Vaquera FdA, Cuenda A MEF2C and MEF2D, SAP1a, c-Myc and CREB. For example, ERK5 phosphorylates SAP1, which enhances its transcriptional activity promoting c-FOS expression (Terasawa et al., 2003), and activates the serum- and glucocorticoid-inducible kinase1 (SGK1) by phosphorylating Ser78 in response to growth factors (Hayashi et al., 2001). In cardiac tissue, ERK5 may couple cells electrically and metabolically by phosphorylating the gap-junction protein Cx43 at a key residue for gap junction communication (Cameron et al., 2003). Also, phosphorylated ERK5 regulates gene expression through its C-terminal transcriptional activation domain (Morimoto et al., 2007). References Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee JD. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature. 1998 Oct 15;395(6703):713-6 Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y, Lee JD. BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoidinducible kinase. J Biol Chem. 2001 Mar 23;276(12):8631-4 Yan C, Luo H, Lee JD, Abe J, Berk BC. Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains. J Biol Chem. 2001 Apr 6;276(14):10870-8 Esparís-Ogando A, Díaz-Rodríguez E, Montero JC, Yuste L, Crespo P, Pandiella A. Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2. Mol Cell Biol. 2002 Jan;22(1):270-85 Homology ERK5 (MAPK7) N-terminal half shares a 50% sequence identity with ERK1/2. The homology of the C-terminal part of ERK5 with other protein has not been reported. ERK5 possesses ortholog in the majority of mammals (sharing 80-98% homology). In C. elegans, the SMA-5 protein is a 60% similar to human ERK5 (Watanabe et al., 2005). In Saccharomyces cerevisiae, Slt2p (Mpk1p) is an ERK5 ortholog (Truman et al., 2006). Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002 Dec 6;298(5600):1912-34 Regan CP, Li W, Boucher DM, Spatz S, Su MS, Kuida K. Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects. Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9248-53 Sohn SJ, Sarvis BK, Cado D, Winoto A. ERK5 MAPK regulates embryonic angiogenesis and acts as a hypoxia-sensitive repressor of vascular endothelial growth factor expression. J Biol Chem. 2002 Nov 8;277(45):43344-51 Mutations Note Not identified. Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C, Lee JD, Abe J, Yang J. Regulation of epidermal growth factorinduced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation. J Biol Chem. 2003 May 16;278(20):18682-8 Implicated in Breast cancer Mody N, Campbell DG, Morrice N, Peggie M, Cohen P. An analysis of the phosphorylation and activation of extracellularsignal-regulated protein kinase 5 (ERK5) by mitogen-activated protein kinase kinase 5 (MKK5) in vitro. Biochem J. 2003 Jun 1;372(Pt 2):567-75 Note ERK5 (MAPK7) expression and activity is increased in breast cancer tumours. ERK5 overexpression has been established as an independent predictor of disease-free survival in breast cancer (Montero et al., 2009). In cell models, ERK5 has been linked to the regulation of breast cancer cells proliferation (Esparís-Ogando et al., 2002). Mulloy R, Salinas S, Philips A, Hipskind RA. Activation of cyclin D1 expression by the ERK5 cascade. Oncogene. 2003 Aug 21;22(35):5387-98 Terasawa K, Okazaki K, Nishida E. Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway. Genes Cells. 2003 Mar;8(3):263-73 Prostatic cancer Yan L, Carr J, Ashby PR, Murry-Tait V, Thompson C, Arthur JS. Knockout of ERK5 causes multiple defects in placental and embryonic development. BMC Dev Biol. 2003 Dec 16;3:11 Note ERK5 (MAPK7) immunoreactivity is significantly upregulated in high-grade prostate cancer. Increased ERK5 cytoplasmic signals correlated with metastases and locally advanced disease at diagnosis. Strong nuclear ERK5 localization in prostatic tumours correlates with poor disease-specific survival (McCracken et al., 2008). Cavanaugh JE. Role of extracellular signal regulated kinase 5 in neuronal survival. Eur J Biochem. 2004 Jun;271(11):2056-9 Hayashi M, Kim SW, Imanaka-Yoshida K, Yoshida T, Abel ED, Eliceiri B, Yang Y, Ulevitch RJ, Lee JD. Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J Clin Invest. 2004 Apr;113(8):1138-48 Barros JC, Marshall CJ. Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton. J Cell Sci. 2005 Apr 15;118(Pt 8):1663-71 Hepatic carcinoma Note An increase in ERK5 (MAPK7) copy number was detected in primary HCC tumours. It has been suggested that MAPK7 is likely the target of 17p11 amplification and that the ERK5 protein promotes the growth of hepatic carcinoma cells by regulating mitotic entry (Zen et al., 2009). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Carvajal-Vergara X, Tabera S, Montero JC, Esparís-Ogando A, López-Pérez R, Mateo G, Gutiérrez N, Parmo-Cabañas M, Teixidó J, San Miguel JF, Pandiella A. Multifunctional role of Erk5 in multiple myeloma. Blood. 2005 Jun 1;105(11):4492-9 Wang X, Merritt AJ, Seyfried J, Guo C, Papadakis ES, Finegan KG, Kayahara M, Dixon J, Boot-Handford RP, Cartwright EJ, 1113 MAPK7 (mitogen-activated protein kinase 7) Iñesta-Vaquera FdA, Cuenda A Mayer U, Tournier C. Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signalregulated kinase 5/myocyte enhancer factor 2 cell survival pathway. Mol Cell Biol. 2005 Jan;25(1):336-45 Sohn SJ, Lewis GM, Winoto A. Non-redundant function of Watanabe N, Nagamatsu Y, Gengyo-Ando K, Mitani S, Ohshima Y. Control of body size by SMA-5, a homolog of MAP kinase BMK1/ERK5, in C. elegans. Development. 2005 Jul;132(14):3175-84 Finegan KG, Wang X, Lee EJ, Robinson AC, Tournier C. Regulation of neuronal survival by the extracellular signalregulated protein kinase 5. Cell Death Differ. 2009 May;16(5):674-83 Kondoh K, Terasawa K, Morimoto H, Nishida E. Regulation of nuclear translocation of extracellular signal-regulated kinase 5 by active nuclear import and export mechanisms. Mol Cell Biol. 2006 Mar;26(5):1679-90 Montero JC, Ocaña A, Abad M, Ortiz-Ruiz MJ, Pandiella A, Esparís-Ogando A. Expression of Erk5 in early stage breast cancer and association with disease free survival identifies this kinase as a potential therapeutic target. PLoS One. 2009;4(5):e5565 the MEK5-ERK5 pathway in thymocyte apoptosis. EMBO J. 2008 Jul 9;27(13):1896-906 Truman AW, Millson SH, Nuttall JM, King V, Mollapour M, Prodromou C, Pearl LH, Piper PW. Expressed in the yeast Saccharomyces cerevisiae, human ERK5 is a client of the Hsp90 chaperone that complements loss of the Slt2p (Mpk1p) cell integrity stress-activated protein kinase. Eukaryot Cell. 2006 Nov;5(11):1914-24 Sawhney RS, Liu W, Brattain MG. A novel role of ERK5 in integrin-mediated cell adhesion and motility in cancer cells via Fak signaling. J Cell Physiol. 2009 Apr;219(1):152-61 Spiering D, Schmolke M, Ohnesorge N, Schmidt M, Goebeler M, Wegener J, Wixler V, Ludwig S. MEK5/ERK5 signaling modulates endothelial cell migration and focal contact turnover. J Biol Chem. 2009 Sep 11;284(37):24972-80 Cude K, Wang Y, Choi HJ, Hsuan SL, Zhang H, Wang CY, Xia Z. Regulation of the G2-M cell cycle progression by the ERK5NFkappaB signaling pathway. J Cell Biol. 2007 Apr 23;177(2):253-64 Zen K, Yasui K, Nakajima T, Zen Y, Zen K, Gen Y, Mitsuyoshi H, Minami M, Mitsufuji S, Tanaka S, Itoh Y, Nakanuma Y, Taniwaki M, Arii S, Okanoue T, Yoshikawa T. ERK5 is a target for gene amplification at 17p11 and promotes cell growth in hepatocellular carcinoma by regulating mitotic entry. Genes Chromosomes Cancer. 2009 Feb;48(2):109-20 Morimoto H, Kondoh K, Nishimoto S, Terasawa K, Nishida E. Activation of a C-terminal transcriptional activation domain of ERK5 by autophosphorylation. J Biol Chem. 2007 Dec 7;282(49):35449-56 McCracken SR, Ramsay A, Heer R, Mathers ME, Jenkins BL, Edwards J, Robson CN, Marquez R, Cohen P, Leung HY. Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer. Oncogene. 2008 May 8;27(21):2978-88 This article should be referenced as such: Iñesta-Vaquera FdA, Cuenda A. MAPK7 (mitogen-activated protein kinase 7). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1111-1114. Schramp M, Ying O, Kim TY, Martin GS. ERK5 promotes Srcinduced podosome formation by limiting Rho activation. J Cell Biol. 2008 Jun 30;181(7):1195-210 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1114