Jonathan Bogan, MD

Dr. Bogan’s laboratory studies molecular mechanisms controlling GLUT4 glucose transporter targeting in adipose and muscle cells. In cell types, insulin stimulates glucose uptake by translocating GLUT4 from intracellular membranes to the cell surface. Understanding how this occurs has been a longstanding puzzle. Dr. Bogan and his coworkers identified proteins that sequester GLUT4 in nonendosomal, intracellular vesicles in the absence of insulin. Insulin then acts on these proteins to mobilize GLUT4 to the cell surface. This action is coordinated with other insulin signals that act on GTPases to direct vesicle targeting. Current work is directed to understand the biochemical mechanisms involved in this response, including phosphorylation, GTPase signaling, and ubiquitin-like modification pathways.

Much current work in the laboratory focuses on a proteolytic mechanism that regulates glucose uptake in fat and muscle. Previous work identified the TUG protein as a critical regulator of GLUT4 targeting, which limits cell-surface GLUT4 and glucose uptake in cells not stimulated with insulin. TUG traps GLUT4 in non-endosomal vesicles, bound at the Golgi matrix and endoplasmic-reticulum intermediate compartment, and insulin triggers site-specific endoproteolytic cleavage of TUG to liberate these vesicles for translocation to the cell surface. GLUT4 and other vesicle cargoes are then maintained at the cell surface by cycling through endosomes until insulin levels falls and the cargoes are re-sequestered. TUG cleavage generates an N-terminal product that functions as a novel ubiquitin-like protein modifier, implicating new enzymatic activities in insulin action. In mice, this proteolytic pathway controls whole-body and muscle-specific glucose uptake, and data show that vesicle cargoes other than GLUT4 regulate vasopressin action. In addition, the TUG C-terminal product enters the nucleus and regulates gene expression to control fatty acid oxidation, thermogenesis, and overall energy expenditure. Thus, regulated TUG cleavage and vesicle translocation coordinates distinct physiologic outputs, and dysregulation of this pathway may contribute to multiple aspects of the metabolic syndrome and obesity.

The pathway that is utilized by GLUT4 is likely one instance of a general pathway to regulate the cell surface targeting of physiologically-important membrane proteins in response to extracellular stimuli. This may involve unconventional secretion of proteins by a Golgi-bypass mechanism, in which proteins are mobilized from the early secretory pathway directly to the plasma membrane. Work on GLUT4 targeting may thus have far-reaching implications for a wide range of physiology. Ongoing work also seeks to understand how particular cells, such as those expressing GLUT4, co-opt general trafficking mechanisms that are present ubiquitously. These studies use a combination of biochemical and cell biological approaches, live cell imaging, genetically engineered mice and studies of organism-level metabolism and physiology.