Disease relevance of MAPK7

• A novel role for extracellular signal-regulated kinase 5 and myocyte enhancer factor 2 in medulloblastoma cell death [1].
• Multifunctional role of Erk5 in multiple myeloma [2].
• These findings reveal a specific role for MEK5-ERK5 in the induction of eccentric cardiac hypertrophy and in transduction of cytokine signals that regulate serial sarcomere assembly [3].
• Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2 [4].
• Inspection of the 17 genes uniquely regulated by ERK5 revealed that 14 genes (82%) were previously associated with hypoxia via regulation by HIF-1 [5].

High impact information on MAPK7

• Expression of a dominant-negative form of Bmk1 blocks EGF-induced cell proliferation and prevents cells from entering the S phase of the cell cycle [6].
• Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor [6].
• Big MAP kinase (Bmk1), also known as Erk5, is a member of the MAP kinase family that is activated in cells in response to oxidative stress, hyperosmolarity and treatment with serum [6].
• ERK5 inhibits the nuclear export of c-Fos by phosphorylating Thr232 in the c-Fos NES(221-233) and disrupts the interaction of c-Fos with UBR1 by phosphorylating Ser32 [7].
• Moreover, UBR1 depletion in HeLa cells, which constitutively express UBR1 at a high level, enhances both c-Fos expression and cell growth, whereas ERK5 depletion reduces both of them [7].

Chemical compound and disease context of MAPK7

• The i.t. administration of ERK5 antisense oligodeoxynucleotide reversed heat hyperalgesia, but not mechanical allodynia, produced by capsaicin injection [8].

Biological context of MAPK7

• These results demonstrate that Bmk1 is part of a distinct MAP-kinase signalling pathway that is required for EGF-induced cell proliferation and progression through the cell cycle [6].
• Thus, through its kinase and transcriptional activation domains, ERK5 regulates transcriptional responses of cell survival and quiescence critical for angiogenesis and T-cell function [9].
• Only those cells expressing MAP/ERK kinase 5 (MEK5) plus ERK5 or MEF2 constructs underwent apoptosis, indicating that overexpression of either is sufficient to induce medulloblastoma cell death [1].
• Dual phosphorylation site mutation of MEK5alpha (Ser-311 --> Asp and Thr- 315 --> Asp; MEK5alpha(S311D/T315D)) activated BMK1, but the corresponding dual phosphorylation sites mutant of MEK5beta could not induce BMK1 kinase activation or nuclear translocation [10].
• These results reveal a novel signaling pathway to the nucleus mediated by ERK5 that functions downstream of receptor tyrosine kinases to induce immediate early genes, in parallel with the classical MAPK cascade [11].

Anatomical context of MAPK7

• To elucidate molecular functions of ERK5 in the development of vasculature and other tissues, we performed gene profile analyses of erk5-/- mouse embryos and erk5-/- fibroblast cells reconstituted with ERK5 or ERK5(1-740), which lacks the transactivation domain [9].
• Overexpression of both ERK5 and MEF2 induced a statistically significant increase in cell death of neurotrophin-3-responsive and nonresponsive medulloblastoma cell lines (Daoy-trkC and Daoy) and primary cultures of patched heterozygous mouse medulloblastomas [1].
• The activation of ERK5 was inhibited by expression of dominant-negative Ras and induced by expression of active Ras in PC12 cells, indicating a requirement for Ras in ERK5 activation [11].
• Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation [12].
• Previous data show that BMK1 can be activated by steady laminar flow and is atheroprotective by preventing endothelial cells from undergoing apoptosis [13].

Associations of MAPK7 with chemical compounds

• Here, we have found that ERK5 is required for mediating the survival of fibroblasts under basal conditions and in response to sorbitol treatment [14].
• Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus [11].
• These data demonstrate an inhibitory function for 14-3-3beta binding to BMK1 and show that serine 486 phosphorylation represents a novel regulatory mechanism for BMK1 [13].
• Although unique in its structure, ERK5 is activated in analogy to other MAPKs by dual phosphorylation of threonine and tyrosine residues in its activation motif [15].
• Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway [15].

Physical interactions of MAPK7

• Here, we report the identification of serum and glucocorticoid-inducible kinase (SGK) as a cellular protein that physically interacts with BMK1 [16].

Enzymatic interactions of MAPK7

• Taken together, these data demonstrate that, upon growth factor induction, BMK1 directly phosphorylates and activates three members of the MEF2 family of transcription factors thereby inducing MEF2-dependent gene expression [17].

Regulatory relationships of MAPK7

• BMK1 (ERK5) regulates squamous differentiation marker SPRR1B transcription in Clara-like H441 cells [18].
• Activation of BMK1/ERK5 by epidermal growth factor and H2O2 in Cos7 and HEK293 cells was completely blocked by a kinase-inactive MEKK3 (MEKK3kin(-)), whereas MEKK2kin(-) had no effect [19].
• The blocking of BMK1 signaling inhibits the epidermal growth factor-dependent activation of these three MEF2 transcription factors [17].
• We have previously shown that BMK1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor MEF2C [17].
• The ability of PMA to partially suppress TRAIL- and TNF-induced cell death was inhibited by BMK1/DN [20].

Other interactions of MAPK7

• Furthermore, by co-immunoprecipitation, we found that BMK1 directly associates with Cx43 in vivo [12].
• Most of the tumors displayed complex amplification profiles, with frequent involvement of marker D17S2041 in 17p12 and TOP3A in 17p11.2 and, in some cases, very high-level amplification of PMP22 and MAPK7 in 17p11 [21].
• Here we show that EGF is a potent activator of Bmk1 [6].
• MEK5 is the upstream BMK1 kinase and exists as naturally occurring splice variants, MEK5alpha and MEK5beta [10].
• The sites phosphorylated by activated BMK1 were mapped to Ser-355, Thr-312, and Thr-319 of MEF2A and Ser-179 of MEF2D both in vitro and in vivo [17].

Analytical, diagnostic and therapeutic context of MAPK7

• In the present study, we investigated the phosphorylation of ERK5, also known as big MAPK1, in the DRG by noxious stimulation using immunohistochemistry [8].
• Notably, during the later phase of reperfusion, the rise in ERK5 activation was strong and persistent with a peak occurring at the third day [22].
• Our results showed that ERK5 was activated selectively in hippocampal CA1 region with, but not without, the ischemic preconditioning [22].
• Phosphorylation of ERK1/2, p38MAP kinase and ERK5 was determined by immunoblotting [23].
• Sequence analysis showed that these cDNAs are alternative splice products of the mouse ERK5 gene [24].

References