Elucidation of the activation mechanisms and functions of ASK1

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Cells are continuously exposed to a wide variety of physical, chemical, and biological stressors from both the external and internal environments. In order to adapt to or resist stress, cells are equipped with multiple signaling systems that elicit a wide range of stress responses. As a component of such signaling systems, we focused on apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) of the c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. In this project, we investigated the molecular mechanisms of ASK1 activation and its function in cell survival and apoptosis as well as cell differentiation. Finally, we demonstrated the following:1) Endogenous ASK1 forms a high molecular mass complex. ASK1 is activated through the dissociation of inhibitory factors from the ASK1 complex followed by the reciprocal recruitment of activation factors to the complex (J. Biol. Chem., 2005).2) We have identified a novel MAP3K, ASK2, which interacts with ASK1. ASK2 plays important roles in stress responses by forming a functional heteromeric complex with ASK1, in which ASK1 and ASK2 facilitate each other's activity by distinct mechanisms (J. Biol. Chem., 2007).3) We have identified a novel protein phosphatase, PGLM, as an interacting protein of ASK1. PGLM appears to activate ASK1 by direct dephosphorylation of the phosphorylation site(s) that inhibits ASK1 activity.4) ASK1 is activated in response to lipopolysaccharide (LPS) through ROS that are produced downstream of TLR4, and plays critical roles in innate immune response through the p38 pathway (Nat. Immunol., 2005).5) ASK1 is required for wounding-induced infiltration and activation of macrophages, and functions as an inducer of wounding-induced hair growth in mice.These findings strongly suggest that ASK1 plays critical roles in cellular response to a variety of stressors as an intermediate of the intracellular signaling system.