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

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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.

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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*

This work was supported by United States Public Health Service Grants MH-084018 (to A. S.), MH-094268 Silvo O. Conte Center (to A. S.), MH-069853 (to A. S.), MH-085226 (to A. S.), MH-088753 (to A. S.), MH-092443 (to A. S.), National Institutes of Health NRSA F31 Grant 1F31NS070459-01A1 (to C. T.), Stanley (to A. S.), RUSK (to A. S.), S-R foundations (to A. S.), NARSAD (to A. S. and N. S.), and Maryland Stem Cell Research Fund (A. S.). This work was also supported in part by Grant-in-aid 22580339 for Scientific Research from the Japan Society for the promotion of Science (to H. N).

1

These authors contributed equally to this work.