Role of apoptosis signal-regulating kinase 1 (ASK1) as an activator of the GAPDH-Siah1 stress-signaling cascade.


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.


Tristan, Carlos; Ramos, Adriana; Shahani, Neelam; Emiliani, Francesco E; Nakajima, Hidemitsu; Noeh, Christopher C; Kato, Yoshinori; Takeuchi, Tadayoshi; Noguchi, Takuya; Kadowaki, Hisae; Sedlak, Thomas W; Ishizuka, Koko; Ichijo, Hidenori; Sawa, Akira;


  • Amino Acid Sequence
  • Binding Sites
  • Gene Expression Regulation
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/ genetics
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/ metabolism
  • HEK293 Cells
  • Humans
  • Hydrogen Peroxide/ pharmacology
  • MAP Kinase Kinase Kinase 5/ genetics
  • MAP Kinase Kinase Kinase 5/ metabolism
  • Molecular Sequence Data
  • Nuclear Proteins/ genetics
  • Nuclear Proteins/ metabolism
  • Oxidative Stress
  • Phosphorylation/ drug effects
  • Protein Binding/ drug effects
  • Recombinant Fusion Proteins/ genetics
  • Recombinant Fusion Proteins/ metabolism
  • Signal Transduction/ genetics
  • Ubiquitin-Protein Ligases/ genetics
  • Ubiquitin-Protein Ligases/ metabolism

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