The overall objectives of this research proposal are to develop a detailed understanding of the intramolecular subunit interactions responsible for mediating the ligand-dependent transmembrane activation of the insulin and IGF-1 receptor tyrosine kinase activities. The mature cell surface receptors function as alpha2/beta2 heterotetrameric complexes composed of two extracellular ligand binding alpha subunits which are disulfide-linked to two transmembrane beta subunits which also contain intracellular tyrosine kinase domains. In addition, to the homologous insulin and IGF-1 alpha2/beta2 holoreceptors, several studies have documented the presence of insulin/IGF-1 hybrid receptors composed of two non-identical alpha beta half-receptor species. In addition, in vitro assembly of wild type and mutant hybrid receptors have been used to characterize several of the functional properties of these receptor species. In this application we propose to determine a molecular basis for transmembrane signalling by utilizing both in vivo and in vitro approaches to generate various hybrid receptor species. In vitro assembly of various receptor hybrid combinations will be used to systematically dissect the specific binding, kinase and intramolecular subunit interactions responsible for ligand- stimulated transmembrane signalling. In addition, the relationship between intramolecular autophosphorylation with that of cross phosphorylation (intermolecular trans) will be assessed. Controlled expression of hybrid receptors in vivo will be used to directly determine the ligand-mediated receptor signalling via the homologous insulin and IGF-1 receptors as well as by the insulin/IGF-1 hybrid receptor species. Further, transgenic mice expressing the wild type and kinase-defective human insulin receptor will be prepared and characterized. The development of a transgenic mouse model of transdominant insulin and/or IGF-1 resistance will be an extremely valuable system to further define the molecular defects associated with certain types of diabetes in vivo..

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033823-12
Application #
2139165
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1984-04-01
Project End
1996-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
12
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Tang, Yan; Kwon, Hyokjoon; Neel, Brian A et al. (2018) The fructose-2,6-bisphosphatase TIGAR suppresses NF-?B signaling by directly inhibiting the linear ubiquitin assembly complex LUBAC. J Biol Chem 293:7578-7591
Tarabra, Elena; An Lee, Ting-Wen; Zammit, Victor A et al. (2017) Differential activation of Fyn kinase distinguishes saturated and unsaturated fats in mouse macrophages. Oncotarget 8:86634-86645
Mansueto, Gelsomina; Armani, Andrea; Viscomi, Carlo et al. (2017) Transcription Factor EB Controls Metabolic Flexibility during Exercise. Cell Metab 25:182-196
McKimpson, Wendy M; Zheng, Min; Chua, Streamson C et al. (2017) ARC is essential for maintaining pancreatic islet structure and ?-cell viability during type 2 diabetes. Sci Rep 7:7019
Martinez-Lopez, Nuria; Tarabra, Elena; Toledo, Miriam et al. (2017) System-wide Benefits of Intermeal Fasting by Autophagy. Cell Metab 26:856-871.e5
Deller, Robert C; Pessin, Jeffrey E; Vatish, Manu et al. (2016) Enhanced non-vitreous cryopreservation of immortalized and primary cells by ice-growth inhibiting polymers. Biomater Sci 4:1079-84
Otero, Yolanda F; Mulligan, Kimberly X; Barnes, Tammy M et al. (2016) Enhanced Glucose Transport, but not Phosphorylation Capacity, Ameliorates Lipopolysaccharide-Induced Impairments in Insulin-Stimulated Muscle Glucose Uptake. Shock 45:677-85
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Wei, Jianwen; Shimazu, Junko; Makinistoglu, Munevver P et al. (2015) Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation. Cell 161:1576-1591
Brima, Wunnie; Eden, Daniel J; Mehdi, Syed Faizan et al. (2015) The brighter (and evolutionarily older) face of the metabolic syndrome: evidence from Trypanosoma cruzi infection in CD-1 mice. Diabetes Metab Res Rev 31:346-359

Showing the most recent 10 out of 130 publications