Jonathan S Bogan MD
Associate Professor of Medicine (Endocrinology) and of Cell Biology
Protein trafficking; Ubiquitin-like modification; Cell structure; Insulin signaling; Type 2 diabetes; Metabolic diseases
Dr. Bogan’s research seeks to understand how glucose uptake is regulated in fat and muscle cells. In these cell types, insulin causes glucose transporters to move from internal membranes to the cell surface. Glucose is then transported into the cells, and is removed from the bloodstream. The regulation of this process is defective in insulin-resistant states such as type 2 diabetes. Dr. Bogan’s laboratory identified regulated proteolytic cleavage as a novel biochemical mechanism to control glucose transporter movement. Current efforts are focused on characterizing this mechanism in detail, and on determining how this pathway controls metabolism and physiology.
Extensive Research Description
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 a protein complex that sequesters GLUT4 in nonendosomal, intracellular vesicles in the absence of insulin. Insulin then acts on this complex 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 insulin triggers endoproteolytic cleavage of TUG to liberate these vesicles for translocation to the cell surface. GLUT4 and other vesicle cargos are then maintained at the cell surface by cycling through endosomes, and they bypass a TUG-regulated compartment until insulin signaling is terminated, and the cargos are re-sequestered. This arrangement obviates the need for ongoing TUG cleavage during sustained insulin exposure. TUG cleavage generates a product that functions as a novel ubiquitin-like protein modifier, implicating new enzymatic activities in insulin action. In mice, this proteolytic pathway controls glucose metabolism and energy expenditure, and data imply that vesicle cargos other than GLUT4 may contribute to the regulation of vasopressin action and lipid metabolism. Thus, regulated TUG cleavage and vesicle translocation may coordinate distinct physiologic outputs, and dysregulation of this pathway may contribute to multiple aspects of the metabolic syndrome.
The pathway that is utilized by GLUT4 is likely one instance of a general pathway to regulate the cell surface targeting of membrane proteins in response to extracellular stimuli. Work on GLUT4 targeting may thus have far-reaching implications for a wide range of physiology. In addition, this regulated pathway is likely a cell type-specific adaptation of a fundamental trafficking pathway present in most cells. Current work will elucidate this pathway and how it is adapted to control GLUT4, using a combination of biochemical and cell biological approaches, genetically engineered mice, and studies of organism-level metabolism and physiology.