Chihiro Sakauchi1, Hiroaki Wakatsuki1, Hidenori Ichijo2, Kazuki Hattori1. 1. The laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 2. The laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: ichijo@mol.f.u-tokyo.ac.jp.
Abstract
BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), has the potential to induce cellular apoptosis under various physiological conditions. It has long been suggested that ASK1 is highly sensitive to oxidative stress and contributes substantially to apoptosis. However, recent studies have indicated that ASK1 has pleiotropic roles in living organisms through other mechanisms in addition to apoptosis. SCOPE OF THE REVIEW: This review describes the physiological functions of ASK1 in living organisms, focusing on the regulatory mechanisms of ASK1 activity and its importance in the pathogenesis of various diseases. We also highlight recent works published within the past few years. MAJOR CONCLUSIONS: ASK1 forms a high-molecular-mass complex within the cell, designated as the ASK1 signalosome. Soon after the discovery of ASK1, several regulatory components of the ASK1 signalosome have been revealed, including thioredoxin (Trx), tumor-necrosis factor α receptor-associated factors (TRAFs) and 14-3-3s. In parallel with the precise analyses unveiling the molecular basis of ASK1 regulation, the physiological or pathophysiological significance of ASK1 in diverse organs has been elucidated. In addition to the generation of global knockout mice or tissue-specific knockout mice, ASK1-specific inhibitors have illuminated the biological roles of ASK1. GENERAL SIGNIFICANCE: The multi-faceted features of the function of ASK1 have been discovered over the past two decades, revealing that ASK1 is a crucial molecule for maintaining cellular homeostasis, especially under conditions of stress. Based on the results that ASK1 deficiency provides beneficial effects for several diseases, modulating ASK1 activity is a promising method to ameliorate a subset of diseases. Copyright Â
BACKGROUND:Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), has the potential to induce cellular apoptosis under various physiological conditions. It has long been suggested that ASK1 is highly sensitive to oxidative stress and contributes substantially to apoptosis. However, recent studies have indicated that ASK1 has pleiotropic roles in living organisms through other mechanisms in addition to apoptosis. SCOPE OF THE REVIEW: This review describes the physiological functions of ASK1 in living organisms, focusing on the regulatory mechanisms of ASK1 activity and its importance in the pathogenesis of various diseases. We also highlight recent works published within the past few years. MAJOR CONCLUSIONS:ASK1 forms a high-molecular-mass complex within the cell, designated as the ASK1 signalosome. Soon after the discovery of ASK1, several regulatory components of the ASK1 signalosome have been revealed, including thioredoxin (Trx), tumor-necrosis factor α receptor-associated factors (TRAFs) and 14-3-3s. In parallel with the precise analyses unveiling the molecular basis of ASK1 regulation, the physiological or pathophysiological significance of ASK1 in diverse organs has been elucidated. In addition to the generation of global knockout mice or tissue-specific knockout mice, ASK1-specific inhibitors have illuminated the biological roles of ASK1. GENERAL SIGNIFICANCE: The multi-faceted features of the function of ASK1 have been discovered over the past two decades, revealing that ASK1 is a crucial molecule for maintaining cellular homeostasis, especially under conditions of stress. Based on the results that ASK1 deficiency provides beneficial effects for several diseases, modulating ASK1 activity is a promising method to ameliorate a subset of diseases. Copyright Â
Authors: Susanne Schuster-Gaul; Lukas Jonathan Geisler; Matthew D McGeough; Casey D Johnson; Anna Zagorska; Li Li; Alexander Wree; Vivian Barry; Igor Mikaelian; Lily J Jih; Bettina G Papouchado; Grant Budas; Hal M Hoffman; Ariel E Feldstein Journal: JCI Insight Date: 2020-01-30