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Novel Crosstalk between Insulin and TGF‐beta signaling in Vascular Endothelial Cells
Author(s) -
Shah Nirav,
Pan Christopher,
Kumar Sanjay,
Zaman Naveed,
Elmasry Fatema,
Lee Nam Y
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.944.12
Subject(s) - endoglin , angiogenesis , crosstalk , signal transduction , insulin receptor , cancer research , transforming growth factor beta , gene knockdown , insulin , endocrinology , medicine , receptor , tgf beta signaling pathway , biology , microbiology and biotechnology , transforming growth factor , insulin resistance , gene , genetics , stem cell , physics , cd34 , optics
Angiogenesis is the formation of new blood vessels from preexisting vasculature, an essential process during development and tumor growth. As a TGF‐β receptor complex primarily expressed in proliferating endothelial cells (ECs), endoglin and ALK1 activate the canonical Smad1/5/8 signaling to promote normal and tumor‐associated angiogenesis. Here we report an unexpected crosstalk between insulin and endoglin/ALK1‐dependent TGF‐b signaling pathways. We found that insulin rapidly activates the canonical TGF‐β and BMP‐9‐induced Smad1/5/8 pathway in numerous EC types tested. Co‐immunoprecipitation, immunofluorescence and targeted knockdown studies reveal that insulin activates Smad1/5/8 through a novel trimeric interaction comprising the insulin receptor, endoglin and ALK1. Importantly, our PCR gene profiling results indicate that insulin‐induced Smad1/5/8 signaling elicits a transcriptional response quite different than those normally activated by TGF‐b or BMP‐9. Given that type 2 diabetic patients are highly susceptible to a number of vascular‐related diseases including proliferative retinopathy, our results strongly implicate aberrant Smad1/5/8 signaling with hyperinsulinemia and insulin resistance during pre‐diabetic and diabetic disease progression. Support or Funding Information RO1 NCI