Chawla Bhavna, Hedman Andrew C, Sayedyahossein Samar, Erdemir Huseyin H, Li Zhigang, Sacks David B
Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892.
Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892.
J Biol Chem. 2017 Feb 24;292(8):3273-3289. doi: 10.1074/jbc.M116.752642. Epub 2017 Jan 12.
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. 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 Collectively, these data reveal that IQGAP1 is a scaffold for IR and IRS-1 and implicate IQGAP1 as a participant in insulin signaling.
胰岛素与胰岛素受体（IR）结合，诱导受体及胰岛素受体底物-1（IRS-1）的酪氨酸磷酸化，从而激活蛋白激酶B/蛋白激酶B（PKB/Akt）和丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）信号通路。IQGAP1是一种支架蛋白，它与多个结合伴侣相互作用，并整合多种信号级联反应。在此我们表明，IQGAP1与IR和IRS-1均相关联，并影响胰岛素作用。对纯蛋白的分析显示，IQGAP1的IQ区域直接与IR的细胞内结构域结合。同样，IRS-1的磷酸酪氨酸结合结构域介导了与IQGAP1 C末端尾巴的直接相互作用。与这些观察结果一致，在细胞中IR和IRS-1均与IQGAP1进行共免疫沉淀。对这些相互作用的功能效应的研究表明，在缺乏IQGAP1的情况下，胰岛素刺激的Akt和ERK磷酸化以及磷脂酰肌醇3激酶与IRS-1的结合均显著降低。重要的是，IQGAP1的缺失导致胰岛素信号传导受损和葡萄糖稳态失衡。总体而言，这些数据表明IQGAP1是IR和IRS-1的支架，并表明IQGAP1参与胰岛素信号传导。
