Coordinate Activation of Redox-Dependent ASK1/TGF-β Signaling by a Multiprotein Complex (MPK38, ASK1, SMADs, ZPR9, and TRX) Improves Glucose and Lipid Metabolism in Mice

Aims: To explore the molecular connections between redox-dependent apoptosis signal-regulating kinase 1 (ASK1) and transforming growth factor-beta (TGF-beta) signaling pathways and to examine the physiological processes in which coordinated regulation of these two signaling pathways plays a critical role. Results: We provide evidence that the ASK1 and TGF-beta signaling pathways are interconnected by a multiprotein complex harboring murine protein serine-threonine kinase 38 (MPK38), ASK1, Sma- and Mad-related proteins (SMADs), zinc-finger-like protein 9 (ZPR9), and thioredoxin (TRX) and demonstrate that the activation of either ASK1 or TGF-beta activity is sufficient to activate both the redox-dependent ASK1 and TGF-beta signaling pathways. Physiologically, the restoration of the downregulated activation levels of ASK1 and TGF-beta signaling in genetically and diet-induced obese mice by adenoviral delivery of SMAD3 or ZPR9 results in the amelioration of adiposity, hyperglycemia, hyperlipidemia, and impaired ketogenesis. Innovation and Conclusion: Our data suggest that the multiprotein complex linking ASK1 and TGF-beta signaling pathways may be a potential target for redox-mediated metabolic complications. Antioxid. Redox Signal. 24, 434-452.