Role of Apoptosis Signal-regulating Kinase 1 (ASK1) as an Activator of the GAPDH-Siah1 Stress-Signaling Cascade |
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Authors: | Carlos A Tristan Adriana Ramos Neelam Shahani Francesco E Emiliani Hidemitsu Nakajima Christopher C Noeh Yoshinori Kato Tadayoshi Takeuchi Takuya Noguchi Hisae Kadowaki Thomas W Sedlak Koko Ishizuka Hidenori Ichijo Akira Sawa |
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Institution: | From the Departments of ‡Psychiatry and ;‡‡Neuroscience.;¶Radiology and Radiological Science.;‖Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.;the §Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka 599-8531, and ;the **Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8654, Japan |
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Abstract: | 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. |
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Keywords: | Nuclear Translocation Oxidative Stress Protein Phosphorylation Protein Translocation Protein-Protein Interaction Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Seven in absentia homolog 1 (Siah1) Apoptosis Signal-regulating Kinase 1 (ASK1) |
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