Ubiquitin-like modification is a conserved biochemical mechanism that is used by cells for various purposes. These include targeted degradation of proteins, endocytosis of receptors, regulation of protein localization, and signal transduction. Apart from a role of ubiquitin itself to modulate insulin receptors and IRS proteins, ubiquitin-like modifications have not been described to play a prominent role in insulin signaling. TUG was identified as a target of insulin signaling, and is implicated regulating GLUT4 glucose transporter trafficking and glucose uptake in adipocytes. According to the proposed model, TUG acts by """"""""tethering"""""""" GLUT4 transporters intracellularly in the absence of insulin, excluding them from the plasma membrane and limiting glucose uptake. Insulin """"""""untethers"""""""" the transporters to redistribute GLUT4 and to enhance glucose transport into cells. The mechanism by which insulin acts on TUG and GLUT4 is not well understood. The present proposal will test the hypothesis that insulin stimulates rapid and site-specific cleavage of TUG to liberate an amino terminal fragment, TUGUL, that is a new ubiquitin-like modifier. Using cultured 3T3-L1 adipocytes, several biochemical and cell biological approaches will be used in Aim 1 to test whether insulin stimulates TUG cleavage, and whether this is required for insulin to mobilize GLUT4.
Aim 2 will test the hypothesis that TUGUL functions as a ubiquitin-like modifier, and will study the role of the putative TUG C terminal cleavage product.
Aim 3 will study how the insulin signal may act on TUG to cause its processing. It is anticipated that, together, accomplishment of these aims will begin to define a novel pathway for insulin regulated ubiquitin-like modification. Furthermore, it is anticipated that the results will have importance for understanding how insulin stimulates glucose uptake. Type 2 diabetes is a major public health problem that results in part from a defect in the ability of insulin to stimulate glucose uptake. It is anticipated that the proposed studies of insulin action and glucose uptake will lead to a greater understanding of mechanisms that may contribute to the development of type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075772-04
Application #
7808840
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Silva, Corinne M
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$297,051
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Xu, Yingke; Toomre, Derek K; Bogan, Jonathan S et al. (2017) Excess cholesterol inhibits glucose-stimulated fusion pore dynamics in insulin exocytosis. J Cell Mol Med 21:2950-2962
Cantley, Jennifer L; Vatner, Daniel F; Galbo, Thomas et al. (2014) 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 307:E773-83
Belman, Jonathan P; Habtemichael, Estifanos N; Bogan, Jonathan S (2014) A proteolytic pathway that controls glucose uptake in fat and muscle. Rev Endocr Metab Disord 15:55-66
Jimenez-Gomez, Yolanda; Mattison, Julie A; Pearson, Kevin J et al. (2013) Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab 18:533-45
Löffler, Michael G; Birkenfeld, Andreas L; Philbrick, Katerina M et al. (2013) Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle. J Biol Chem 288:20135-50
Vatner, Daniel F; Weismann, Dirk; Beddow, Sara A et al. (2013) Thyroid hormone receptor-? agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. Am J Physiol Endocrinol Metab 305:E89-100
Bogan, Jonathan S; Rubin, Bradley R; Yu, Chenfei et al. (2012) Endoproteolytic cleavage of TUG protein regulates GLUT4 glucose transporter translocation. J Biol Chem 287:23932-47
Bogan, Jonathan S; Xu, Yingke; Hao, Mingming (2012) Cholesterol accumulation increases insulin granule size and impairs membrane trafficking. Traffic 13:1466-80
Nakatsu, Fubito; Baskin, Jeremy M; Chung, Jeeyun et al. (2012) PtdIns4P synthesis by PI4KIII? at the plasma membrane and its impact on plasma membrane identity. J Cell Biol 199:1003-16
Bogan, Jonathan S (2012) Regulation of glucose transporter translocation in health and diabetes. Annu Rev Biochem 81:507-32

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