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

Background: 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. 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.