Jonathan S. Bogan, M.D

Assistant Professor of Medicine (Endocrinology) and Cell Biology
Phone: (203) 785-6319 Lab: (203) 785-3405 Fax: (203) 785-6462 e-mail: jonathan.bogan@yale.edu		Section of Endocrinology and Metabolism Department of Internal Medicine 333 Cedar Street P.O. Box 208020 New Haven, CT 06520-8020 USA <Courier Address> 1 Gilbert Street, TAC S141B New Haven, CT 06519

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Our laboratory studies cell biological processes important for the control of metabolism. 
We focus primarily on how insulin and other stimuli regulate the intracellular trafficking of membrane proteins, particularly the GLUT4 glucose transporter.  In mammalian fat and muscle cells, the rate of glucose uptake is controlled by the number of glucose transporters present in the plasma membrane.  In unstimulated cells, endocytosed GLUT4 is specifically and efficiently sorted away from proteins that recycle constitutively at the cell surface, and accumulates in small, poorly characterized, intracellular vesicles termed “GLUT4-storage vesicles” (GSVs).  Because GLUT4 is sequestered away from the plasma membrane, glucose uptake is restricted.  Insulin acts rapidly to mobilize this sequestered GLUT4, inserting the transporters into the plasma membrane to enhance glucose uptake from the extracellular space.  Defects in basal and insulin-stimulated GLUT4 targeting have been implicated in the development of “insulin resistance” in humans, which in turn frequently leads to type 2 diabetes.  Thus, how GLUT4 trafficking is regulated has potentially enormous clinical importance, in addition to its significance as a fundamental question in cell biology.

We identified TUG as a critical regulator of GLUT4 trafficking, using a functional screen in mammalian cells.  TUG binds specifically to GLUT4 and, in unstimulated cells, retains it in intracellular, nonendosomal membranes that have characteristics of GSVs.  Possibly, TUG may link GLUT4 to an intracellular structure and/or constrain an intracellular cycle involving GSVs and trans-Golgi network or endosomal membranes.  Insulin stimulates the dissociation of GLUT4 from TUG to mobilize GLUT4 to the cell surface and augment glucose uptake.  TUG controls the size of the insulin-mobilizable pool of GLUT4, and experiments using RNAi further implicate this step as a major site of GLUT4 regulation.  Thus, our working model is that TUG traps endocytosed GLUT4 and “tethers” it intracellularly, and that insulin mobilizes this pool of retained GLUT4 by releasing this tether.

Current work aims to test and expand upon this model.  In particular, we want to understand the biochemical mechanisms involved in mobilizing GLUT4 from TUG, which may include phosphorylation, GTPase signaling, and ubiquitin-like modification pathways.  We are identifying and studying components of a TUG-GLUT4 complex, with the goal of understanding the detailed mechanism by which TUG retains GLUT4 intracellularly in the absence of insulin.  In addition, we are using genetically engineered mice to study the importance of this cellular process for organism-level glucose homeostasis, and to test its relevance to diabetes pathophysiology.  Finally, a long term goal is to reconstitute mechanisms involved in GLUT4 retention and mobilization using a cell-free system.  We anticipate that this work will have significance both for fundamental mechanisms of regulated protein trafficking, and more directly for diabetes pathophysiology.

 

Fig. 1. A model for GLUT4 glucose transporter trafficking.  Endocytosed GLUT4 is efficiently sorted away from constitutively recycling proteins such as the transferrin receptor, and accumulates in intracellular “GLUT4 storage vesicles” (GSVs).  In unstimulated cells, GSVs may recycle at the trans-Golgi network (as shown) and/or exchange with endosomes.  Insulin mobilizes these vesicles to the cell surface (green arrow) to enhance glucose uptake.  TUG and other proteins selectively retain GLUT4 in GSVs of unstimulated cells, and insulin stimulates the release of GLUT4 from TUG to mobilize the GSVs to the cell surface.

Selected Publications

Yu C, Cresswell J, Löffler MG, and Bogan JS.  The Glucose Transporter 4-regulating Protein TUG Is Essential for Highly Insulin-responsive Glucose Uptake in 3T3-L1 Adipocytes.  Journal of Biological Chemistry 2007; 282:7710-7722.

Tettamanzi MC, Yu C, Bogan JS, and Hodsdon ME.  Solution structure and backbone dynamics of an N-terminal ubiquitin-like domain in the GLUT4-regulating protein, TUG.  Protein Science 2006; 15:498-508.

Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, and Lodish HF. T-cadherin is a receptor for hexameric and high molecular weight  forms of Acrp30/adiponectin.  Proceedings of the National Academy of Sciences USA 2004; 101:10308-10313.

Bogan JS (corresponding author), Hendon N, McKee AE, Tsao TS, and Lodish HF.  Functional cloning of TUG as a regulator of GLUT4 glucose transporter trafficking.  Nature 2003; 425:727-733.

Bogan JS, McKee AE, and Lodish HF.  Insulin-Responsive Compartments Containing GLUT4 in 3T3-L1 and CHO Cells: Regulation by Amino Acid Concentrations.  Molecular and Cellular Biology 2001; 21:4785-4806.

Liu X, Constantinescu SN, Sun Y, Bogan JS, Hirsch D, Weinberg RA, and Lodish HF. Generation of Mammalian Cells Stably Expressing Multiple Genes at Predetermined Levels.  Analytical Biochemistry 2000; 280:20-28.

Bogan JS, and Lodish HF.  Two Compartments for Insulin-stimulated Exocytosis in 3T3-L1 Adipocytes Defined by Endogenous ACRP30 and GLUT4.  Journal of Cell Biology 1999; 146:609-620.