Absence of IQGAP1 impairs insulin signaling and leads to insulin resistance

Authors

• AC Hedman
• B Chawla
• S Sayedyahossein
• HH Erdemir
• Z Li
• DB Sacks

Abstract

Insulin binds to the insulin receptor (IR), inducing receptor autophosphorylation and phosphorylation of the receptor associated protein, insulin receptor substrate-1 (IRS-1). Activated IRS-1 directly interacts with and activates phosphatidylinositol-3-kinase (PI3K), promoting PKB/Akt signaling. This is an essential pathway for normal insulin action, and impaired insulin signaling is a key deficiency in diabetes. IQGAP1 is a scaffold protein that interacts with multiple binding partners to modulate and integrate cellular signaling cascades in response to diverse stimuli. Since IQGAP1 binds to several growth factor receptors and is a component of receptor signaling pathways, we hypothesized that IQGAP1 may participate in insulin signaling. We tested this hypothesis using several strategies, including binding assays with pure proteins, cultured cells and knockout mouse models. Here we demonstrate that IQGAP1 associates with both IR and IRS-1 and modulates insulin signaling. In vitro, IQGAP1 directly interacts with the intracellular domain of IR and with the phosphotyrosine binding domain (PTB) of IRS-1. Additionally, IR and IRS-1 co-immunoprecipitate with IQGAP1 from cells. Further, the function of this interaction in modulating insulin signaling was investigated using knockout models. Experiments performed in IQGAP1-null cells revealed that the absence of IQGAP1 significantly reduced the ability of insulin to stimulate phosphorylation of IRS-1 and Akt, indicating defects in insulin signaling. Importantly, loss of IQGAP1 significantly impaired glucose homeostasis in vivo. Collectively, these data implicate IQGAP1 as a participant in insulin signaling.

Scientific Focus Area: Molecular Biology and Biochemistry

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