The continuing overall objective of this research proposal is to determine the molecular mechanisms accounting for the intracellular trafficking and insulin-stimulated translocation of the GLUT4 glucose transporter protein from intracellular storage sites to the plasma membrane. Over the past several years, substantial progress has been made in our understanding of the insulin signaling pathways and GLUT4 trafficking compartments involved in the translocation process. However, our understanding is still largely incomplete and there remain numerous questions and processes that remain enigmatic. Recently, we have found that entry of the newly synthesized GLUT4 protein in adipocytes acquires insulin responsiveness by direct entry into the insulin-responsive compartments without transiting the plasma membrane or undergoing endocytosis. This has created a new paradigm to examine the targeting machinery and vesicle trafficking events that function at the different membrane transport steps in the GLUT4 lifecycle. To determine the molecular basis for initial GLUT4 cargo selection, trafficking through the secretory pathway and subsequent acquisition of insulin responsiveness, we propose to: 1) to define the specific GLUT4 targeting motifs, the role of known interacting partners and signals that are responsible for the direct transport from the Golgi to the insulin-responsive GLUT4 compartment (GSC) and those responsible from plasma membrane endocytosis to the GSC; 2) to identify the specific role of GGA and PACS1 in the anterograde and retrograde transport of GLUT4 into the GSC; 3) to use recently established Golgi/TGN in vitro vesicle budding assay to identify specific elements in GLUT4 responsible for GGA selectivity for proteomic analysis of donor, total released and GLUT4 specific vesicle-associated proteins; and 4) to determine the role of reversible GLUT4 oligomerization in the retention and release of intracellular GLUT4 and/or its role in the apparent enhancement of GLUT4 transport activity following plasma membrane translocation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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Huang, Ping; Yeku, Oladapo; Zong, Haihong et al. (2011) Phosphatidylinositol-4-phosphate-5-kinase alpha deficiency alters dynamics of glucose-stimulated insulin release to improve glucohomeostasis and decrease obesity in mice. Diabetes 60:454-63
Capilla, Encarnación; Díaz, Mònica; Hou, June Chunqiu et al. (2010) High basal cell surface levels of fish GLUT4 are related to reduced sensitivity of insulin-induced translocation toward GGA and AS160 inhibition in adipocytes. Am J Physiol Endocrinol Metab 298:E329-36
Zong, Haihong; Bastie, Claire C; Xu, Jun et al. (2009) Insulin resistance in striated muscle-specific integrin receptor beta1-deficient mice. J Biol Chem 284:4679-88
Li, Lin V; Bakirtzi, Kyriaki; Watson, Robert T et al. (2009) The C-terminus of GLUT4 targets the transporter to the perinuclear compartment but not to the insulin-responsive vesicles. Biochem J 419:105-12, 1 p following 112
Hou, June Chunqiu; Williams, Dumaine; Vicogne, Jerome et al. (2009) The glucose transporter 2 undergoes plasma membrane endocytosis and lysosomal degradation in a secretagogue-dependent manner. Endocrinology 150:4056-64
Procino, Giuseppe; Barbieri, Claudia; Tamma, Grazia et al. (2008) AQP2 exocytosis in the renal collecting duct -- involvement of SNARE isoforms and the regulatory role of Munc18b. J Cell Sci 121:2097-106
Williams, Dumaine; Pessin, Jeffrey E (2008) Mapping of R-SNARE function at distinct intracellular GLUT4 trafficking steps in adipocytes. J Cell Biol 180:375-87
Min, Le; Leung, Yuk M; Tomas, Alejandra et al. (2007) Dynamin is functionally coupled to insulin granule exocytosis. J Biol Chem 282:33530-6
Hou, June Chunqiu; Pessin, Jeffrey E (2007) Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking. Curr Opin Cell Biol 19:466-73
Capilla, Encarnacion; Suzuki, Naoko; Pessin, Jeffrey E et al. (2007) The glucose transporter 4 FQQI motif is necessary for Akt substrate of 160-kilodalton-dependent plasma membrane translocation but not Golgi-localized (gamma)-ear-containing Arf-binding protein-dependent entry into the insulin-responsive storage compartmen Mol Endocrinol 21:3087-99

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