Absence of IQGAP1 impairs insulin signaling and leads to insulin resistance

FARE Award Winner

Authors

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

Abstract

Insulin binds to the insulin receptor (IR) and induces tyrosine phosphorylation of both the receptor and insulin receptor substrate-1 (IRS-1), leading to activation of the PKB/Akt and MAPK pathways. IQGAP1 is a scaffold protein that interacts with multiple binding partners and integrates diverse signaling cascades. Here we show that IQGAP1 associates with both IR and IRS-1, thereby influencing insulin action. In vitro analysis with pure proteins revealed that the IQ region of IQGAP1 binds directly to the intracellular domain of IR. Similarly, the phosphotyrosine-binding (PTB) domain of IRS-1 mediates a direct interaction with the C-terminal tail of IQGAP1. A multiprotein complex comprising pure IR, IRS-1 and IQGAP1 was observed in vitro. Consistent with these observations, both IR and IRS-1 co-immunoprecipitated with IQGAP1 from cells. Investigation of the functional effects of the interactions revealed that insulin-stimulated phosphorylation of IRS-1, Akt and ERK was significantly decreased in the absence of IQGAP1. Importantly, loss of IQGAP1 results in impaired glucose homeostasis in vivo. Collectively, these data reveal that IQGAP1 is a scaffold for IR and IRS-1 and implicate IQGAP1 as a participant in insulin signaling.

Scientific Focus Area: Molecular Biology and Biochemistry

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