Jonathan S. Bogan, M.D. Assistant Professor Section of Endocrinology Department of Internal Medicine 333 Cedar Street P.O. Box 208020 New Haven, CT 06520-8020 USA Email: jonathan.bogan@yale.edu Telephone: (203) 785-6319 Fax: (203) 785-6015

• B.S., (Engineering) Yale University, 1986
• M.D., (Genetics) Harvard Medical School, 1992
• Intern and Resident in Medicine, Massachusetts General Hospital, 1992-94
• Clinical and Research Fellow, Endocrine Division, Massachusetts General Hospital, 1994-98
• Visiting Scientist, Whitehead Institute for Biomedical Research, 1995-2002
• Instructor in Medicine, Harvard Medical School and Massachusetts General Hospital, 1998-2001
• Assistant Professor of Medicine, Harvard Medical School and Massachusetts General Hospital, 2001-02
• Assistant Professor of Internal Medicine, Yale University School of Medicine 2002-present

Research

Our work focuses on the molecular mechanisms by which insulin regulates glucose uptake and utilization in fat and muscle. The GLUT4 glucose transporter is expressed almost exclusively in these tissues, and the number and activity of these transporters at the cell surface controls the rate of glucose uptake. Insulin acts within minutes to redistribute GLUT4 glucose transporters from an intracellular location to the cell surface, thereby enhancing glucose uptake in a highly regulated manner. This action of insulin is defective in individuals with type 2 diabetes or pre-diabetic (insulin-resistant) physiology. Thus, a detailed knowledge of how insulin controls GLUT4 trafficking is essential to a full understanding of the defects underlying type 2 diabetes.

The control of GLUT4 trafficking is also of significant interest as a fundamental problem in cell biology. Unlike proteins that recycle constitutively at the plasma membrane, GLUT4 is efficiently retained within cells in the absence of insulin, and is targeted to a post-endosomal compartment that remains poorly characterized. The major effect of insulin is to mobilize this pool of retained GLUT4 to the plasma membrane. Though insulin regulation of GLUT4 trafficking is specific to particular cell types (e.g. fat and muscle), similar molecular mechanisms may apply in the endocrine or paracrine regulation of other transporters, ion channels, and receptors.

Our major contribution to this area has been twofold. First, we developed an assay to measure the relative proportion of GLUT4 at the plasma membrane, using flow cytometry to measure a ratio of fluorescence intensities corresponding to the cell surface and total amounts of a doubly-tagged GLUT4 reporter in individual, living cells. Second, we used this assay, together with retoviral vectors we developed, in a functional screen to identify proteins that govern GLUT4 distribution. We identified TUG, a novel protein that functions as a Tether, containing a ubiquitin-like UBX domain, for GLUT4. Data indicate a model in which TUG binds GLUT4 glucose transporters and retains them intracellularly in the absence of insulin. Then, insulin releases this tether to mobilize the retained glucose transporters and to target them to the cell surface.

Current work focuses on the molecular mechanisms by which insulin acts through TUG to control GLUT4 glucose transporter trafficking, and hence glucose uptake. Our work is primarily at the cellular and biochemical level, and we are particularly interested in the role of ubiquitin-like modification mechanisms. Longer-term projects will study the physiologic function of TUG in organism-level glucose homeostasis, and will clarify whether alterations in this mechanism may contribute to the pathophysiology underlying insulin resistance.

Representative Publications

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.

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 , 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.

Bogan JS *, 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. * corresponding author.

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.