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
We study how extracellular stimuli regulate protein trafficking, and specifically
how insulin controls the targeting of GLUT4 glucose transporter proteins.
In mammalian fat and muscle, insulin stimulates glucose uptake by translocating
GLUT4 from intracellular membranes to the cell surface.
We 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. We want to understand the biochemical mechanisms involved in this response, which include phosphorylation, GTPase signaling, and ubiquitin-like modification pathways.
In addition, we are studying the importance of particular components for organism-level glucose homeostasis, using genetically engineered mice. A long-term goal is to reconstitute mechanisms involved in GLUT4 mobilization using a cell-free system. We anticipate that this work will have direct importance for human diabetes as well as fundamental significance for mechanisms of regulated membrane protein trafficking.
Extensive Research Description
Dr. Bogan’s research seeks to understand how glucose uptake is regulated in fat and muscle cells. In these cell types, insulin causes GLUT4 glucose transporters to move from internal membranes to the cell surface. GLUT4 can then transport glucose into the cells, removing it from the bloodstream. This process is defective in insulin-resistant states such as type 2 diabetes.
Dr. Bogan’s laboratory identified a previously uncharacterized protein, TUG, as a major regulator of GLUT4 targeting and glucose uptake. TUG binds GLUT4 and traps it intracellularly in fat cells not exposed to insulin, causing the accumulation of GLUT4 transporters in specialized “insulin-responsive vesicles.” Insulin stimulates the release of GLUT4 from TUG, thus mobilizing GLUT4 to the cell surface to enhance glucose uptake. Current work is directed to understand how and where TUG retains GLUT4 within unstimulated cells, and how insulin acts on a GLUT4-TUG protein complex to cleave TUG and liberate GLUT4. A second area of research studies the control of glucose uptake in muscle, and examines importance of these pathways for overall glucose homeostasis and energy metabolism. Finally, studies are now underway to determine how dysregulated GLUT4 targeting may contribute to insulin resistance.