Cell Biology; Diabetes Mellitus, Type 2; Endocrinology; Glucose; Metabolic Diseases; Protein Transport
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 and glucose uptake. Current efforts are focused on characterizing this mechanism in detail, and on determining how this pathway controls metabolism and physiology.
Specialized Terms: Protein trafficking; Ubiquitin-like modification; Cell structure; Insulin signaling; Type 2 diabetes; Metabolic diseases
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 show that vesicle cargos other than GLUT4 contribute to the regulation of vasopressin action and, possibly, lipid metabolism. 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.
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.
Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action.
Xu Y, Nan D, Fan J, Bogan JS, Toomre D. Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action. Journal of Cell Science 2016;129:2085-95.
Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle.
Habtemichael EN, Alcázar-Román A, Rubin BR, Grossi LR, Belman JP, Julca O, Löffler MG, Li H, Chi NW, Samuel VT, and Bogan JS. Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle. Journal of Biological Chemistry 2015; 290:14454–14461.
Acetylation of TUG Protein Promotes the Accumulation of GLUT4 Glucose Transporters in an Insulin-Responsive Intracellular Compartment.
Belman JP, Bian RR, Habtemichael EN, Li DT, Jurczak MJ, Alcázar-Román A, McNally LJ, Shulman GI, and Bogan JS. Acetylation of TUG Protein Promotes the Accumulation of GLUT4 Glucose Transporters in an Insulin-Responsive Intracellular Compartment. Journal of Biological Chemistry 2015; 290:4447–4463.
A proteolytic pathway that controls glucose uptake in fat and muscle.
Belman JP, Habtemichael EN, and Bogan JS. A proteolytic pathway that controls glucose uptake in fat and muscle. Reviews in Endocrine and Metabolic Disorders 2014; 15:55–66.
Enhanced Fasting Glucose Turnover in Mice with Disrupted Action of TUG Protein in Skeletal Muscle.
Löffler MG, Birkenfeld AL, Philbrick KM, Belman JP, Habtemichael EN, Booth CJ, Castorena CM, Choi CS, Jornayvaz FR, Gassaway BM, Lee H-Y, Cartee GD, Philbrick W, Shulman GI, Samuel VT, and Bogan JS. Enhanced Fasting Glucose Turnover in Mice with Disrupted Action of TUG Protein in Skeletal Muscle. Journal of Biological Chemistry 2013; 288:20135–20150.
Endoproteolytic Cleavage of TUG Protein Regulates GLUT4 Glucose Transporter Translocation.
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.
Regulation of Glucose Transporter Translocation in Health and Diabetes.
Bogan JS. Regulation of Glucose Transporter Translocation in Health and Diabetes. Annual Review of Biochemistry 2012; 81:507–32.
The Ubiquitin Regulatory X (UBX) Domain-containing Protein TUG Regulates the p97 ATPase and Resides at the Endoplasmic Reticulum–Golgi Intermediate Compartment.
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.
Dual-Mode of Insulin Action Controls GLUT4 Vesicle Exocytosis.
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.
Full List of PubMed Publications
- Tol MJ, Ottenhoff R, van Eijk M, Zelcer N, Aten J, Houten SM, Geerts D, van Roomen C, Bierlaagh MC, Scheij S, Hoeksema MA, Aerts JM, Bogan JS, Dorn GW 2nd, Argmann CA, Verhoeven AJ: A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity. Diabetes. 2016 Sep; 2016 Jun 20. PMID: 27325287
- Xu Y, Nan D, Fan J, Bogan JS, Toomre D: Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action. J Cell Sci. 2016 May 15; 2016 Apr 13. PMID: 27076519
- Habtemichael EN, Alcázar-Román A, Rubin BR, Grossi LR, Belman JP, Julca O, Löffler MG, Li H, Chi NW, Samuel VT, Bogan JS: Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle. J Biol Chem. 2015 Jun 5; 2015 May 5. PMID: 25944897
- Belman JP, Bian RR, Habtemichael EN, Li DT, Jurczak MJ, Alcázar-Román A, McNally LJ, Shulman GI, Bogan JS: Acetylation of TUG protein promotes the accumulation of GLUT4 glucose transporters in an insulin-responsive intracellular compartment. J Biol Chem. 2015 Feb 13; 2015 Jan 5. PMID: 25561724
- Castorena CM, Arias EB, Sharma N, Bogan JS, Cartee GD: Fiber type effects on contraction-stimulated glucose uptake and GLUT4 abundance in single fibers from rat skeletal muscle. Am J Physiol Endocrinol Metab. 2015 Feb 1; 2014 Dec 9. PMID: 25491725
- Cantley JL, Vatner DF, Galbo T, Madiraju A, Petersen M, Perry RJ, Kumashiro N, Guebre-Egziabher F, Gattu AK, Stacy MR, Dione DP, Sinusas AJ, Ragolia L, Hall CE, Manchem VP, Bhanot S, Bogan JS, Samuel VT: Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats. Am J Physiol Endocrinol Metab. 2014 Nov 1; 2014 Aug 26. PMID: 25159329
- Bogan JS: Endocytic cycling of glucose transporters and insulin resistance due to immunosuppressive agents. J Clin Endocrinol Metab. 2014 Oct. PMID: 25279573
- Belman JP, Habtemichael EN, Bogan JS: A proteolytic pathway that controls glucose uptake in fat and muscle. Rev Endocr Metab Disord. 2014 Mar. PMID: 24114239
- Jimenez-Gomez Y, Mattison JA, Pearson KJ, Martin-Montalvo A, Palacios HH, Sossong AM, Ward TM, Younts CM, Lewis K, Allard JS, Longo DL, Belman JP, Malagon MM, Navas P, Sanghvi M, Moaddel R, Tilmont EM, Herbert RL, Morrell CH, Egan JM, Baur JA, Ferrucci L, Bogan JS, Bernier M, de Cabo R: Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 2013 Oct 1. PMID: 24093677
- Löffler MG, Birkenfeld AL, Philbrick KM, Belman JP, Habtemichael EN, Booth CJ, Castorena CM, Choi CS, Jornayvaz FR, Gassaway BM, Lee HY, Cartee GD, Philbrick W, Shulman GI, Samuel VT, Bogan JS: Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle. J Biol Chem. 2013 Jul 12; 2013 Jun 6. PMID: 23744065
- Vatner DF, Weismann D, Beddow SA, Kumashiro N, Erion DM, Liao XH, Grover GJ, Webb P, Phillips KJ, Weiss RE, Bogan JS, Baxter J, Shulman GI, Samuel VT: Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. Am J Physiol Endocrinol Metab. 2013 Jul 1; 2013 May 7. PMID: 23651850
- Bogan JS, Xu Y, Hao M: Cholesterol accumulation increases insulin granule size and impairs membrane trafficking. Traffic. 2012 Nov; 2012 Sep 13. PMID: 22889194
- Bogan JS, Rubin BR, Yu C, Löffler MG, Orme CM, Belman JP, McNally LJ, Hao M, Cresswell JA: Endoproteolytic cleavage of TUG protein regulates GLUT4 glucose transporter translocation. J Biol Chem. 2012 Jul 6; 2012 May 18. PMID: 22610098
- Orme CM, Bogan JS: The ubiquitin regulatory X (UBX) domain-containing protein TUG regulates the p97 ATPase and resides at the endoplasmic reticulum-golgi intermediate compartment. J Biol Chem. 2012 Feb 24; 2011 Dec 29. PMID: 22207755
- Bogan JS: Regulation of glucose transporter translocation in health and diabetes. Annu Rev Biochem. 2012; 2012 Apr 5. PMID: 22482906
- Castorena CM, Mackrell JG, Bogan JS, Kanzaki M, Cartee GD: Clustering of GLUT4, TUG, and RUVBL2 protein levels correlate with myosin heavy chain isoform pattern in skeletal muscles, but AS160 and TBC1D1 levels do not. J Appl Physiol (1985). 2011 Oct; 2011 Jul 28. PMID: 21799128
- Xu Y, Rubin BR, Orme CM, Karpikov A, Yu C, Bogan JS, Toomre DK: Dual-mode of insulin action controls GLUT4 vesicle exocytosis. J Cell Biol. 2011 May 16; 2011 May 9. PMID: 21555461
- Bogan JS, Kandror KV: Biogenesis and regulation of insulin-responsive vesicles containing GLUT4. Curr Opin Cell Biol. 2010 Aug; 2010 Apr 21. PMID: 20417083
- Paranjape SA, Chan O, Zhu W, Horblitt AM, McNay EC, Cresswell JA, Bogan JS, McCrimmon RJ, Sherwin RS: Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo. Diabetes. 2010 Jun; 2010 Mar 18. PMID: 20299468
- McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS: Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010 May; 2010 Feb 20. PMID: 20176121
- Hao M, Bogan JS: Cholesterol regulates glucose-stimulated insulin secretion through phosphatidylinositol 4,5-bisphosphate. J Biol Chem. 2009 Oct 23; 2009 Sep 3. PMID: 19729450
- Orme CM, Bogan JS: Cell biology. Sorting out diabetes. Science. 2009 May 29. PMID: 19478173
- Nagai Y, Yonemitsu S, Erion DM, Iwasaki T, Stark R, Weismann D, Dong J, Zhang D, Jurczak MJ, Löffler MG, Cresswell J, Yu XX, Murray SF, Bhanot S, Monia BP, Bogan JS, Samuel V, Shulman GI: The role of peroxisome proliferator-activated receptor gamma coactivator-1 beta in the pathogenesis of fructose-induced insulin resistance. Cell Metab. 2009 Mar. PMID: 19254570
- Rubin BR, Bogan JS: Intracellular retention and insulin-stimulated mobilization of GLUT4 glucose transporters. Vitam Horm. 2009. PMID: 19251038
- Yu C, Cresswell J, Löffler MG, Bogan JS: The glucose transporter 4-regulating protein TUG is essential for highly insulin-responsive glucose uptake in 3T3-L1 adipocytes. J Biol Chem. 2007 Mar 9; 2007 Jan 3. PMID: 17202135
- Tettamanzi MC, Yu C, Bogan JS, Hodsdon ME: Solution structure and backbone dynamics of an N-terminal ubiquitin-like domain in the GLUT4-regulating protein, TUG. Protein Sci. 2006 Mar. PMID: 16501224
- Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish HF: T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci U S A. 2004 Jul 13; 2004 Jun 21. PMID: 15210937
- Bogan JS, Hendon N, McKee AE, Tsao TS, Lodish HF: Functional cloning of TUG as a regulator of GLUT4 glucose transporter trafficking. Nature. 2003 Oct 16. PMID: 14562105
- Bogan JS, McKee AE, Lodish HF: Insulin-responsive compartments containing GLUT4 in 3T3-L1 and CHO cells: regulation by amino acid concentrations. Mol Cell Biol. 2001 Jul. PMID: 11416153
- Liu X, Constantinescu SN, Sun Y, Bogan JS, Hirsch D, Weinberg RA, Lodish HF: Generation of mammalian cells stably expressing multiple genes at predetermined levels. Anal Biochem. 2000 Apr 10. PMID: 10805516
- Bogan JS, Lodish HF: Two compartments for insulin-stimulated exocytosis in 3T3-L1 adipocytes defined by endogenous ACRP30 and GLUT4. J Cell Biol. 1999 Aug 9. PMID: 10444069
- Katznelson L, Bogan JS, Trob JR, Schoenfeld DA, Hedley-Whyte ET, Hsu DW, Zervas NT, Swearingen B, Sleeper M, Klibanski A: Biochemical assessment of Cushing's disease in patients with corticotroph macroadenomas. J Clin Endocrinol Metab. 1998 May. PMID: 9589666
- Bogan JS, Page DC: Ovary? Testis?--A mammalian dilemma. Cell. 1994 Feb 25. PMID: 8124705
- Behlke MA, Bogan JS, Beer-Romero P, Page DC: Evidence that the SRY protein is encoded by a single exon on the human Y chromosome. Genomics. 1993 Sep. PMID: 8244390
- Vollrath D, Foote S, Hilton A, Brown LG, Beer-Romero P, Bogan JS, Page DC: The human Y chromosome: a 43-interval map based on naturally occurring deletions. Science. 1992 Oct 2. PMID: 1439769
- Cantrell MA, Bogan JS, Simpson E, Bicknell JN, Goulmy E, Chandler P, Pagon RA, Walker DC, Thuline HC, Graham JM Jr: Deletion mapping of H-Y antigen to the long arm of the human Y chromosome. Genomics. 1992 Aug. PMID: 1505957