Role of Apoptosis Signal-regulating Kinase 1 (ASK1) as an Activator of the GAPDH-Siah1 Stress-Signaling Cascade

作者：Carlos A. Tristan, Adriana Ramos, Neelam Shahani, Francesco E. Emiliani, Hidemitsu Nakajima, Christopher C. Noeh, Yoshinori Katō, Tadayoshi Takeuchi, Takuya Noguchi, Hisae Kadowaki, Thomas W. Sedlak, Koko Ishizuka, Hidenori Ichijo, Akira Sawa · 发表于：Journal of Biological Chemistry · 年份：2014 · DOI：10.1074/jbc.m114.596205 · 被引用次数：24 · 研究领域：Molecular Biology Techniques and Applications、Heat shock proteins research、Redox biology and oxidative stress

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays roles in both energy maintenance, and stress signaling by forming a protein complex with seven in absentia homolog 1 (Siah1). Mechanisms to coordinate its glycolytic and stress cascades are likely to be very important for survival and homeostatic control of any living organism. Here we report that apoptosis signal-regulating kinase 1 (ASK1), a representative stress kinase, interacts with both GAPDH and Siah1 and is likely able to phosphorylate Siah1 at specific amino acid residues (Thr-70/Thr-74 and Thr-235/Thr-239). Phosphorylation of Siah1 by ASK1 triggers GAPDH-Siah1 stress signaling and activates a key downstream target, p300 acetyltransferase in the nucleus. This novel mechanism, together with the established S -nitrosylation/oxidation of GAPDH at Cys-150, provides evidence of how the stress signaling involving GAPDH is finely regulated. In addition, the present results imply crosstalk between the ASK1 and GAPDH-Siah1 stress cascades.Apoptosis signal-regulating kinase 1 (ASK1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and seven in absentia homolog 1 (Siah1) are molecules associated with stress-signaling cascades. Results Identification of Siah1 as a substrate of ASK1 for activation of the GAPDH-Siah1 signaling cascade. Conclusion ASK1 triggers the GAPDH-Siah1 stress-signaling cascade. Significance This study provides insight into crosstalk among cell stress-signaling cascades.