Departments of Cell and Tissue Biology, and Anatomy, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA, 94143-0669, USA.
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892-1906, USA.
Sci Rep. 2019 Nov 18;9(1):16992. doi: 10.1038/s41598-019-53490-x.
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.
胰岛素信号转导调控多种生理过程，包括葡萄糖稳态和代谢，临床上用于治疗糖尿病的高血糖。我们证明，胰岛素诱导的 Akt 激活通过从细胞内 TGF-β 受体池中增加细胞表面 TGF-β 受体来增强 TGF-β 的敏感性。因此，胰岛素诱导的自分泌 TGF-β 信号增加参与了内皮细胞的胰岛素诱导的血管生成反应。由于 TGF-β 信号转导调控多种细胞反应，包括分化和细胞外基质沉积，并病理性促进纤维化和癌细胞扩散，我们研究了自分泌 TGF-β 信号在多大程度上参与了胰岛素诱导的人内皮细胞基因反应。在不存在或存在 TGF-β 受体激酶抑制剂的情况下，对胰岛素反应的转录组分析揭示了自分泌 TGF-β 信号在胰岛素反应性基因反应中具有显著的正和负贡献。此外，许多基因的胰岛素诱导反应依赖于或源自自分泌 TGF-β 信号。我们的分析还强调了自分泌 TGF-β 信号对无胰岛素时基础基因表达的广泛贡献，并鉴定出许多新的 TGF-β 反应基因。该数据资源可能有助于了解自分泌 TGF-β 信号在胰岛素对正常生理反应中的作用，以及治疗性胰岛素使用的影响。
