Integration of TGF-?-induced Smad signaling in the insulin-induced transcriptional response in endothelial cells.

ABSTRACT: Insulin signaling governs many processes including glucose homeostasis and metabolism, and is therapeutically used to treat hyperglycemia in diabetes. We demonstrated that insulin-induced Akt activation enhances the sensitivity to TGF-? by directing an increase in cell surface TGF-? receptors from a pool of intracellular TGF-? receptors. Consequently, increased autocrine TGF-? signaling in response to insulin participates in insulin-induced angiogenic responses of endothelial cells. With TGF-? signaling controlling many cell responses, including differentiation and extracellular matrix deposition, and pathologically promoting fibrosis and cancer cell dissemination, we addressed to which extent autocrine TGF-? signaling participates in insulin-induced gene responses of human endothelial cells. Transcriptome analyses of the insulin response, in the absence or presence of a TGF-? receptor kinase inhibitor, revealed substantial positive and negative contributions of autocrine TGF-? signaling in insulin-responsive gene responses. Furthermore, insulin-induced responses of many genes depended on or resulted from autocrine TGF-? signaling. Our analyses also highlight extensive contributions of autocrine TGF-? signaling to basal gene expression in the absence of insulin, and identified many novel TGF-?-responsive genes. This data resource may aid in the appreciation of the roles of autocrine TGF-? signaling in normal physiological responses to insulin, and implications of therapeutic insulin usage.

SUBMITTER: Budi EH 

PROVIDER: S-EPMC6861289 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature