Absence of IQGAP1 Protein Leads to Insulin Resistance

作者：Chawla Bhavna; Hedman Andrew C; Sayedyahossein Samar; Erdemir Huseyin H; Li Zhigang; Sacks David B

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2017, 292(8): 3273-3289.

DOI：10.1074/jbc.M116.752642

<jats:p>Insulin binds to the insulin receptor (IR) and induces tyrosine phosphorylation of the receptor and insulin receptor substrate-1 (IRS-1), leading to activation of the PKB/Akt and MAPK/ERK 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 and influences insulin action. <jats:italic>In vitro</jats:italic> analysis with pure proteins revealed that the IQ region of IQGAP1 binds directly to the intracellular domain of IR. Similarly, the phosphotyrosine-binding domain of IRS-1 mediates a direct interaction with the C-terminal tail of IQGAP1. 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 in the absence of IQGAP1, insulin-stimulated phosphorylation of Akt and ERK, as well as the association of phosphatidylinositol 3-kinase with IRS-1, were significantly decreased. Importantly, loss of IQGAP1 results in impaired insulin signaling and glucose homeostasis <jats:italic>in vivo</jats:italic>. Collectively, these data reveal that IQGAP1 is a scaffold for IR and IRS-1 and implicate IQGAP1 as a participant in insulin signaling.</jats:p>

• 出版日期2017-2-24