Jonathan S Bogan MD

Associate Professor of Medicine (Endocrinology) and of Cell Biology

Research Interests

Protein trafficking; Ubiquitin-like modification; Cell structure; Insulin signaling; Type 2 diabetes; Metabolic diseases

Research Summary

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.

Selected Publications

  • Löffler MG, Birkenfeld AL, Philbrick KM, Belman JP, Habtemichael EN, Booth CJ, Castorena CM, Choi CS, Jornayvaz FR, Lee H-Y, Cartee GD, Booth CJ, Philbrick WP, Shulman GI, Samuel VT, and Bogan JS. Enhanced fasting glucose turnover in mice with disrupted TUG action in skeletal muscle. Journal of Biological Chemistry 2013; 288:20135-20150.
  • Bogan JS, Rubin BR, Yu C, Löffler MG, Orme CM, Belman JP, McNally LJ, Hao M, and Cresswell JC. Endoproteolytic Cleavage of TUG Protein Regulates GLUT4 Glucose Transporter Translocation. Journal of Biological Chemistry 2012; 287:23932-23947.
  • Bogan JS. Regulation of Glucose Transporter Translocation in Health and Diabetes. Annual Review of Biochemistry 2012; 81:507–32.
  • Orme CM and Bogan JS. The Ubiquitin Regulatory X (UBX) Domain-containing Protein TUG Regulates the p97 ATPase and Resides at the Endoplasmic Reticulum–Golgi Intermediate Compartment. Journal of Biological Chemistry 2012; 287:6679-6692.
  • Xu Y, Rubin BR, Orme CM, Karpikov A, Yu C, Bogan JS*, and Toomre D* (*equal contribution; co-corresponding authors). Dual-Mode of Insulin Action Controls GLUT4 Vesicle Exocytosis. Journal of Cell Biology 2011; 193:643–653.
  • Hao M and Bogan JS. Cholesterol Regulates Glucose-stimulated Insulin Secretion through Phosphatidylinositol 4,5-Bisphosphate. Journal of Biological Chemistry 2009; 284:29489-29498.
  • Yu C, Cresswell J, Löffler MG, and Bogan JS. The Glucose Transporter 4-regulating Protein TUG Is Essential for Highly Insulin-responsive Glucose Uptake in 3T3-L1 Adipocytes. Journal of Biological Chemistry 2007; 282:7710-7722.

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