MAPK7 (mitogen-activated protein kinase 7)

Alias_names	PRKM7
Alias_symbol (synonym)	BMK1
	ERK5
Other alias	ERK4
HGNC (Hugo)	MAPK7
LocusID (NCBI)	5598
Atlas_Id	41294
Location	17p11.2  [Link to chromosome band 17p11]
Location_base_pair	Starts at 19378461 and ends at 19383544 bp from pter ( according to hg19-Feb_2009)  [Mapping MAPK7.png]
	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.
Description	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 (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).
Pseudogene	No human or mouse pseudogene known.

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. 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.
	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.
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 is widely expressed throughout all tissues.
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 C-terminal halves is disrupted, and therefore ERK5 enters the nucleus (Kondoh et al., 2006).
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 ERK5-NFKappaB 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, 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).
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).

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