title: Absence of IQGAP1 Protein Leads to Insulin Resistance.
abstract: 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.In vitroanalysis 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 homeostasisin vivoCollectively, these data reveal that IQGAP1 is a scaffold for IR and IRS-1 and implicate IQGAP1 as a participant in insulin signaling.
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Chawla
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Hedman
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Samar
authors.initials: S
authors.lastname: Sayedyahossein
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Huseyin H
authors.initials: HH
authors.lastname: Erdemir
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland 20892. Electronic address: david.sacks2@nih.gov.
authors.forename: David B
authors.initials: DB
authors.lastname: Sacks
mesh_terms: D000818:Animals; D002460:Cell Line; D017353:Gene Deletion; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D010766:Phosphorylation; D060066:Protein Interaction Maps; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C101203:IQ motif containing GTPase activating protein 1; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D020703:ras GTPase-Activating Proteins; D011972:Receptor, Insulin
keywords: Akt PKB; IQGAP1; insulin; insulin receptor; insulin receptor substrate 1 (IRS-1); insulin resistance; mitogen-activated protein kinase (MAPK); phosphatidylinositide 3-kinase (PI 3-kinase)