Coordinate regulation of ASK1/TGF‐β signaling contributes to improved glucose and lipid metabolism in mice

Abstract

We explore the molecular connections between ASK1 and TGF‐β signaling pathways and examine the physiological processes in which coordinate regulation of these two signaling pathways plays a critical role. ASK1 and TGF‐β signaling pathways are interconnected by complex containing Smad proteins (Smad2, 3, 4, and 7) and ZPR9, a zinc finger protein, under the control of apoptosis signal‐regulating kinase 1 (ASK1) and its upstream kinase, murine protein serine‐threonine kinase 38 (MPK38), and a signal for either ASK1 or TGF‐β activity is sufficient to activate both ASK1 and TGF‐β signaling pathways via phosphorylation of Smad(s) and ZPR9 by ASK1 and MPK38. The Smad(s)‐ZPR9 complex is required for the coordinate regulation of ASK1 and TGF‐β signaling in response to ASK1 or TGF‐β signals. We also defined Smad(s) as differential regulators for ASK1 and its downstream targets (MKK3, p38, and JNK), as well as ZPR9 as a regulator of Smad(s) stability. In the physiological setting, restoration of down‐regulated ASK1 and TGF‐β signaling in a genetic mouse model of obesity by adenoviral delivery of Smad3 or ZPR9 resulted in the amelioration of hyperglycemia and hyperlipidemia.