Distinct signaling by insulin and IGF-1 receptors and their extra- and intracellular domains

Abstract

Insulin and insulin-like growth factor 1 (IGF-1) receptors share many downstream signaling pathways but have unique biological effects. To define the molecular signals contributing to these distinct activities, we performed global phosphoproteomics on cells expressing either insulin receptor (IR), IGF-1 receptor (IGF1R), or chimeric IR-IGF1R receptors. We show that IR preferentially stimulates phosphorylations associated with mammalian target of rapamycin complex 1 (mTORC1) and Akt pathways, whereas IGF1R preferentially stimulates phosphorylations on proteins associated with the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases), and cell cycle progression. There were also major differences in the phosphoproteome between cells expressing IR versus IGF1R in the unstimulated state, including phosphorylation of proteins involved in membrane trafficking, chromatin remodeling, and cell cycle. In cells expressing chimeric IR-IGF1R receptors, these differences in signaling could be mapped to contributions of both the extra- and intracellular domains of these receptors. Thus, despite their high homology, IR and IGF1R preferentially regulate distinct networks of phosphorylation in both the basal and stimulated states, allowing for the unique effects of these hormones on organismal function.

Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis

“…Hence, one possible explanation for our data is a ligand-independent role of tip cell insulin receptors. Indeed, recent data from Ronald Kahn’s group indicate a ligand-independent role of insulin receptors in the membrane trafficking of brown pre-adipocytes ( 46 ), potentially aligning with our findings. However, although the concentrations of insulin experienced by sprouting endothelial cells in vivo are unknown, our in vitro data are likely to reflect low picomolar concentrations of insulin because of its presence in fetal calf serum.…”

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