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Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation
Kohsuke Takeda1, Atsushi Matsuzawa, Hideki Nishitoh
1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, and CREST, Japan Science and Technology Corporation, Hongo, Tokyo, Japan.
Abstract:
The mammalian mitogen-activated protein (MAP) kinase kinase kinase apoptosis signal-regulating kinase 1 (ASK1) is a pivotal component in cytokine- and stress-induced apoptosis. It also regulates cell differentiation and survival through p38 MAP kinase activation. Here we show that Ca2+ signalling regulates the ASK1-p38 MAP kinase cascade. Ca2+ influx evoked by membrane depolarization in primary neurons and synaptosomes induced activation of p38, which was impaired in those derived from ASK1-deficient mice. Ca2+/calmodulin-dependent protein kinase type II (CaMKII) activated ASK1 by phosphorylation. Moreover, p38 activation induced by the expression of constitutively active CaMKII required endogenous ASK1. Thus, ASK1 is a critical intermediate of Ca2+ signalling between CaMKII and p38 MAP kinase.