Mitogen Activated Protein Kinases

MAP kinases participate in signal transduction classically associated with cell proliferation, differentiation, and death.l02 Of the major mammalian MAP kinases, ERKl/2, p38 MAP kinase, and JNK are the best characterized. ERKl/2, phosphorylated by MEKl/2 (MAP/ERK kinase), is a key growth signaling kinase, whereas JNK and p38 MAP kinase, phosphorylated by MEK4/7 and MEK3/6, respectively, influence cell survival, apoptosis, differentiation, and inflammation.l()2 ERK5, a recently identified MAP kinase, is regulated by MEK5 and is involved in protein synthesis, cell cycle progression, and cell growth^02 Enhanced activation of vascular MAP kinases has been demonstrated in hypertension and seems to be a major mechanism contributing to vascular damage in hypertension.l03l(4 MAP kinases are regulated by phosphorylation cascades^02 In addition these kinases are activated by ROS or by a mild oxidative shift of the intracellular thiol/disulfide redox stated05 In VSMCs intracellular ROS are critical for Ang II-induced activation of p38MAPK, JNK, and ERK5, whereas phosphorylation of ERKl/2 appears to be redox-insensi-tive.l06l(7 However, serotonin-mediated ERKl/2 activation in smooth muscle cells is redox-sensitive, but in fibroblasts, it is not,l0!i suggesting that redox-regulation of MAP kinases may be ligand- and cell-specific. Although MAP kinases are influenced by free radicals, they are probably not direct substrates of ¬ĽO2- and H2O2. Upstream modulators such as MEKs, tyrosine kinases, and phosphatases may be direct targets.

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