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-β by directing an increase in cell surface TGF-β receptors from a pool of intracellular TGF-β receptors. Consequently, increased autocrine TGF-β signaling in response to insulin participates in insulin-induced angiogenic responses of endothelial cells. With TGF-β 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-β 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-β receptor kinase inhibitor, revealed substantial positive and negative contributions of autocrine TGF-β signaling in insulin-responsive gene responses. Furthermore, insulin-induced responses of many genes depended on or resulted from autocrine TGF-β signaling. Our analyses also highlight extensive contributions of autocrine TGF-β signaling to basal gene expression in the absence of insulin, and identified many novel TGF-β-responsive genes. This data resource may aid in the appreciation of the roles of autocrine TGF-β signaling in normal physiological responses to insulin, and implications of therapeutic insulin usage.
Highlights
Cell responses to extracellular ligands often lead to changes in gene expression, resulting from receptor-mediated activation of signaling pathways
We reported that Akt activation in response to insulin induces a rapid increase in cell surface TGF-β receptors in fibroblasts, epithelial cells, and endothelial cells, through mobilization of TGF-β receptors from an intracellular pool to the cell surface[13,14]
We previously reported that insulin increases TGF-β responsiveness and autocrine TGF-β /Smad signaling by promoting the transport of TGF-β receptors to the cell surface, and that this stimulation of TGF-β receptor transport results from insulin-induced Akt activation[14]
Summary
Cell responses to extracellular ligands often lead to changes in gene expression, resulting from receptor-mediated activation of signaling pathways. These target genes through post-translational modifications and changes in chromatin binding of DNA-binding transcription factors. To address the extent to which insulin-induced upregulation of autocrine TGF-β signaling contributes to insulin-induced gene expression, we carried out genome-wide RNA-Seq analyses of human umbilical vein endothelial cells (HuVECs). Venn analyses of the differentially expressed genes identified numerous genes that integrate TGF-β/Smad signaling into the insulin-induced response, and these genes associate with a variety of biological responses and signaling pathways. We demonstrate that basal gene expression of endothelial cells in the absence of insulin depends on autocrine TGF-β signaling
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