The goal of the present proposal is to study cross-talk between G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) that are present in physiological condition in renal mesangial cells. Specifically, we will study the involvement of metalloproteinases in this process. Further, we wish to study how extracellular matrix (ECM) receptors (called integrins) influence GPCR-RTK cross-talk in cultured mesangial cells.
The specific aims of this proposal are: 1. To investigate whether activation of mitogenic Gq-coupled receptors (such as angiotensin II AT1A, serotonin 5-HT2A and LPA-Edg receptors) induce transactivation of the epidermal growth factor receptor (EGFR) by exogenous growth factor(s) through metalloproteinases in renal mesangial cells. a) If yes, we will examine whether these processes involve the same EGF-like growth factor (namely heparin-bound EGF) or whether distinct EGF-like growth factors are employed by the various GPCRs. b) We will also determine whether these shed ligands are processed by the same metalloproteinase(s), or by different ones depending on which GPCR is activated. Our initial focus will be on the TACE/ADAM 17 metalloproteinase. 2. To study the involvement of integrins and effects of changes in the ECM on GPCR-RTK cross-talk in mesangial cells. a) Is Gq-coupled receptor activation of ERK dependent on integrin-mediated cell anchorage? b) Which integrins are involved in GPCR-RTK cross-talk? c) Does overexpression of a TACE enzyme lacking the disintegrin domain alter signaling? d) Is physical interaction of TACE with integrins necessary for the GPCR-RTK cross-talk to occur?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK070054-05
Application #
7612711
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2005-06-01
Project End
2010-11-30
Budget Start
2009-06-01
Budget End
2010-11-30
Support Year
5
Fiscal Year
2009
Total Cost
$111,238
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Gooz, Pal; Dang, Yujing; Higashiyama, Shigeki et al. (2012) A disintegrin and metalloenzyme (ADAM) 17 activation is regulated by ?5?1 integrin in kidney mesangial cells. PLoS One 7:e33350
Bell, Hannah L; Gööz, Monika (2010) ADAM-17 is activated by the mitogenic protein kinase ERK in a model of kidney fibrosis. Am J Med Sci 339:105-7
Saha, Arindam; Backert, Steffen; Hammond, Charles E et al. (2010) Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit. Gastroenterology 139:239-48
Gooz, Monika (2010) ADAM-17: the enzyme that does it all. Crit Rev Biochem Mol Biol 45:146-69
Dey, Mamon; Baldys, Aleksander; Sumter, Dezmond B et al. (2010) Bradykinin decreases podocyte permeability through ADAM17-dependent epidermal growth factor receptor activation and zonula occludens-1 rearrangement. J Pharmacol Exp Ther 334:775-83
Göoz, Pal; Göoz, Monika; Baldys, Aleksander et al. (2009) ADAM-17 regulates endothelial cell morphology, proliferation, and in vitro angiogenesis. Biochem Biophys Res Commun 380:33-8
Gooz, Monika; Gooz, Pal; Luttrell, Louis M et al. (2006) 5-HT2A receptor induces ERK phosphorylation and proliferation through ADAM-17 tumor necrosis factor-alpha-converting enzyme (TACE) activation and heparin-bound epidermal growth factor-like growth factor (HB-EGF) shedding in mesangial cells. J Biol Chem 281:21004-12