Serine-Threonine Kinase Receptor-associated Protein Inhibits Apoptosis Signal-regulating Kinase 1 Function through Direct Interaction
Copyright policy )Serine-Threonine Kinase Receptor-associated Protein Inhibits Apoptosis Signal-regulating Kinase 1 Function through Direct Interaction
Serine-threonine kinase receptor-associated protein (STRAP) interacts with transforming growth factor beta (TGF-beta) receptors and inhibits TGF-beta signaling. Here, we identify STRAP as an interacting partner of ASK1 (apoptosis signal-regulating kinase 1). The association between ASK1 and STRAP is mediated through the C-terminal domain of ASK1 and the fourth and sixth WD40 repeats of STRAP. Using cysteine-to-serine amino acid substitution mutants of ASK1 (C1005S, C1351S, C1360S, and C1351S/C1360S) and STRAP (C152S, C270S, and C152S/C270S), we demonstrated that Cys(1351) and Cys(1360) of ASK1 and Cys(152) and Cys(270) of STRAP are required for ASK1-STRAP binding. ASK1 phosphorylated STRAP at Thr(175) and Ser(179), suggesting a potential role for STRAP phosphorylation in ASK1 activity regulation. Expression of wild-type STRAP, but not STRAP mutants (C152S/C270S and T175A/S179A), inhibited ASK1-mediated signaling to both JNK and p38 kinases by stabilizing complex formation between ASK1 and its negative regulators, thioredoxin and 14-3-3, or decreasing complex formation between ASK1 and its substrate MKK3. In addition, STRAP suppressed H(2)O(2)-mediated apoptosis in a dose-dependent manner by inhibiting ASK1 activity through direct interaction. These results suggest that STRAP can act as a negative regulator of ASK1.
- Chungbuk National University Korea (Republic of)
Caspase 3, MAP Kinase Signaling System, MAP Kinase Kinase 3, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Apoptosis, Hydrogen Peroxide, MAP Kinase Kinase Kinase 5, Cell Line, Neoplasm Proteins, Enzyme Activation, Mice, Phosphoserine, Phosphothreonine, 14-3-3 Proteins, Protein Interaction Mapping, Animals, Humans, Phosphorylation, Protein Binding
Caspase 3, MAP Kinase Signaling System, MAP Kinase Kinase 3, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Apoptosis, Hydrogen Peroxide, MAP Kinase Kinase Kinase 5, Cell Line, Neoplasm Proteins, Enzyme Activation, Mice, Phosphoserine, Phosphothreonine, 14-3-3 Proteins, Protein Interaction Mapping, Animals, Humans, Phosphorylation, Protein Binding
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