title: GIV/girdin binds exocyst subunit-Exo70 and regulates exocytosis of GLUT4 storage vesicles.
abstract: Insulin resistance (IR) is a metabolic disorder characterized by impaired glucose uptake in response to insulin. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the chief conduit for post-receptor signaling. We recently demonstrated that GIV, a Guanidine Exchange Factor (GEF) for the trimeric G protein, Gαi, is a major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind the InsR, IRS1 and PI3K, GIV enhances the InsR-IRS1-Akt-AS160 (RabGAP) signaling cascade and cellular glucose uptake via its GEF function. Phosphoinhibition of GIV-GEF by the fatty-acid/PKCθ pathway inhibits the cascade and impairs glucose uptake. Here we show that GIV directly and constitutively binds the exocyst complex subunit Exo-70 and also associates with GLUT4-storage vesicles (GSVs) exclusively upon insulin stimulation. Without GIV or its GEF function, membrane association of Exo-70 as well as exocytosis of GSVs in response to insulin are impaired. Thus, GIV is an essential component within the insulin signaling cascade that couples upstream signal transducers within the InsR and G-Protein signaling cascade to downstream vesicular trafficking events within the exocytic pathway. These findings suggest a role of GIV in coordinating key signaling and trafficking events of metabolic insulin response.
authors.affiliation: Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Lopez-Sanchez
authors.affiliation: Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Ma
authors.affiliation: Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Pedram
authors.affiliation: Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kalogriopoulos
authors.affiliation: Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA; Department of Cell and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA. Electronic address: prghosh@ucsd.edu.
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D002460:Cell Line; D005089:Exocytosis; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: C502451:CCDC88A protein, human; C547754:EXOC7 protein, human; D051275:Glucose Transporter Type 4; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins
keywords: Akt; Exocyst complex; Exocytosis; Exo−70; Girdin/GIV; Glucose transporter/GLUT4; PI3−Kinase