Our work focuses on how insulin regulates glucose uptake and, more broadly, how extra cellular stimuli regulate protein trafficking.  In fat and muscle, insulin acts rapidly to redistribute GLUT4 glucose transporters from intracellular membranes to the plasma membrane.  The number of these transporters at the cell surface controls the overall rate of glucose uptake, and the regulation of GLUT4 distribution is defective in insulin resistant states such as type 2 diabetes.  We identified TUG as a protein that binds GLUT4 and traps it intracellularly, thus excluding GLUT4 from the cell surface and restricting glucose uptake, in the absence of insulin.  Insulin liberates GLUT4 from TUG, mobilizing the transporters to the plasma membrane and enhancing glucose uptake.  Our current work seeks to understand how TUG acts to sequester GLUT4 intracellularly in the absence of insulin, and how insulin acts upon a TUG-GLUT4 protein complex to mobilize GLUT4.  We have also initiated experiments using transgenic mice to study the importance of this mechanism for the overall control of glucose homeostasis.  In longer range work, we want to reconstitute the biochemical mechanisms involved in this regulation using a cell free system.  We hope these studies will shed light generally on mechanisms for hormone-regulated protein trafficking, as well as more specifically on physiology and pathophysiology relevant to diabetes.

Yu C, Cresswell J, Löffler MG, and Bogan JS.  The GLUT4 regulating protein TUG is essential for highly insulin responsive glucose uptake in 3T3-L1 adipocytes.  J Biol Chem 2007 (in press).

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.  Proc Nat Acad Sci USA 2004; 101:10308-10313.

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.

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.