Disease relevance of Mapk7

• We propose a novel role for BMK1 in protecting the heart from ischemia/reperfusion-induced cardiac injury [1].
• Big MAP kinase 1 (BMK1/ERK5) plays a critical role in pre-natal development of the cardiovascular system and post-natal eccentric hypertrophy of the heart [1].
• Activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion [1].
• Histological analysis revealed that, after BMK1 ablation, hemorrhages occurred in multiple organs in which endothelial cells lining the blood vessels became round, irregularly aligned, and, eventually, apoptotic [2].
• Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutation [3].

High impact information on Mapk7

• An active form of MEF2C could partially bypass the requirement for BMK1 for endothelial cell survival in vitro [4].
• Physiological analysis showed that the blood vessels became abnormally leaky after deletion of the BMK1 gene [2].
• Big mitogen-activated protein kinase 1 (BMK1), also known as ERK5, is a member of the MAPK family [2].
• Conditional gene deletion showed BMK1 to be required for survival of endothelial cells [4].
• We generated a BMK1 conditional mutation in mice in which disruption of the BMK1 gene is under the control of the inducible Mx1-Cre transgene [2].

Biological context of Mapk7

• Overall, this is the first study to rigorously establish the role of MEK5 in vivo as an activator of ERK5 and as an essential regulator of cell survival that is required for normal embryonic development [5].
• Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signal-regulated kinase 5/myocyte enhancer factor 2 cell survival pathway [5].
• These experiments showed that Src was essential for ERK1/2 and also ERK5 phosphorylation by asbestos [6].
• We conclude that LIGHT overrides Leukemia inhibitory factor to induce ES cell differentiation associated with activation of ERK5 [7].
• Pre-adipocytes expressing DNFTalpha or treated with PD98059 were unable to differentiate to mature adipocytes, whereas pre-adipocytes transfected with ERK5 siRNA showed moderate inhibition of insulin-induced adipogenesis [8].

Anatomical context of Mapk7

• We have investigated the role of MEF2C activation in mast cells and demonstrated that it requires sequential activation of the signaling cascade of MEKK2-MEK5-ERK5 [9].
• Endothelial cells that line the developing myocardium of erk5-/- embryos displayed a disorganized, rounded morphology [10].
• ERK5 is activated by forskolin, isoproterenol, and epinephrine in NIH3T3 cells and C2C12 myoblasts [11].
• LIGHT induces differentiation of mouse embryonic stem cells associated with activation of ERK5 [7].
• MEKK2 regulates the coordinate activation of ERK5 and JNK in response to FGF-2 in fibroblasts [12].

Associations of Mapk7 with chemical compounds

• A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: a role for c-Jun NH2-terminal kinase, p38s, and extracellular signal-regulated kinase 5 [13].
• ERK5 activity is increased by agents known to activate receptor tyrosine kinases, G-protein coupled receptors, and stress response pathways [11].
• Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice [14].
• When ERK5 was inhibited by the specific inhibitor PD184352 or knocked down by ERK5 siRNA, reduction of Oct-4 and SSEA-1 expression was rescued [7].
• The level of BMK1 activation markedly decreased by replacement of tyrosine 1062 with phenylalanine (designated Y1062F) in RET, indicating the importance of downstream signaling via tyrosine 1062 [3].
• We show that the activated kinase activity of ERK5 is required for the C-terminal-half to enhance the AP-1 activity, and that the activated ERK5 undergoes autophosphorylation on its most C-terminal region [15].

Physical interactions of Mapk7

• However, the identification of MEK5alpha mutants with selective binding defect demonstrates that the MEK5/ERK5 interaction does not rely on the binding of MEK5alpha to MEKK2 via their respective PB1 domains [16].
• A novel mitogen-activated protein kinase docking site in the N terminus of MEK5alpha organizes the components of the extracellular signal-regulated kinase 5 signaling pathway [16].

Enzymatic interactions of Mapk7

• Activated MEK5 then phosphorylates and activates ERK5 [17].

Regulatory relationships of Mapk7

• MEKK2 coordinately activates the ERK5 and JNK pathways [12].
• In the present study, we investigated whether glial cell line-derived neurotrophic factor (GDNF) can induce activation of BMK1 through RET tyrosine kinase [3].
• In addition, we detected BMK1 activation in NIH3T3 cells expressing RET with a multiple endocrine neoplasia (MEN) 2A mutation [3].

Other interactions of Mapk7

• We generated cardiac-specific constitutively active form of the MEK5alpha (CA-MEK5alpha transgenic (Tg) mice), and observed a 3 to 4-fold increase in endogenous BMK1 activation and hyperphosphorylation of connexin 43 in the ventricles of the Tg compared to wild-type mice [1].
• Moreover, in addition to JNK, ERK5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements [13].
• These results demonstrate the novel and important, MEKK2-dependent role of MEF2C in induction of c-Jun expression in mast cells activated through FcepsilonRI, a pathway distinct from that involving MEKK2-MEK5-ERK5 in the regulation of mast cell cytokine production [9].
• ERK1/2 are also activated by cAMP in NIH3T3 cells, but not in C2C12 myoblasts, demonstrating differential regulation of ERK5 and ERK1/2 by cAMP [11].
• ERK5-deficient embryos are embryonic lethal due to defects in angiogenesis and cardiovascular development [18].

Analytical, diagnostic and therapeutic context of Mapk7

• RESULTS: To help determine the function of ERK5 we have used gene targeting to inactivate this gene in mice [19].

References