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

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 ...