application) This application outlines the research and career plan proposed by Dr. Peter P. Sayeski concerning the role of the non-receptor tyrosine kinase, Jak2, in mediating angiotensin II growth responses. Angiotensin II is the effector molecule of the renin-angiotensin-aldosterone system which maintains hemodynamic and electrolyte homeostasis. The binding of angiotensin II to the AT1 receptor initiates tyrosine phosphorylation signaling cascades which end with increased vasoconstrictive and mitogenic growth responses. The pharmacologic inhibition of this system has been advantageous in a variety of common diseases including hypertension, heart failure and diabetic nephropathy. In response to angiotensin II, Jak2 forms a physical co-association with the AT1 receptor. Previous work by Dr. Sayeski and others suggest that Jak2 plays a critical role in mediating these tyrosine phosphorylation growth responses. The idea that the growth promoting effects of angiotensin II are dependent on Jak2 tyrosine kinase and not heterotrimeric G proteins is a novel concept. This application is designed to directly test this hypothesis. The proposed experiments in this application are based on preliminary data using newly created recombinant DNA molecules and novel cell lines. Completion of the proposed Specific Aims will provide a better understanding of (1) the biochemical nature of the AT1/Jak2 physical co-association and (2) the specific role of Jak2 in mediating angiotensin II-dependent mitogenic growth responses. The research will be performed at Emory University which contains state of the art facilities and programs that foster the development of young scientific investigators.

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 #
1K01DK060471-01
Application #
6415649
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2001-05-01
Project End
2004-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
1
Fiscal Year
2001
Total Cost
$89,413
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Godeny, Michael D; Sayeski, Peter P (2007) Jak2 tyrosine kinase and cancer: how good cells get HiJAKed. Anticancer Agents Med Chem 7:643-50
Ma, Xianyue; Sayeski, Peter P (2007) Identification of tubulin as a substrate of Jak2 tyrosine kinase and its role in Jak2-dependent signaling. Biochemistry 46:7153-62
Godeny, Michael D; Sayyah, Jacqueline; VonDerLinden, Dannielle et al. (2007) The N-terminal SH2 domain of the tyrosine phosphatase, SHP-2, is essential for Jak2-dependent signaling via the angiotensin II type AT1 receptor. Cell Signal 19:600-9
Wallace, Tiffany A; Sayeski, Peter P (2006) Jak2 tyrosine kinase: a mediator of both housekeeping and ligand-dependent gene expression? Cell Biochem Biophys 44:213-22
Godeny, Michael D; Sayeski, Peter P (2006) ERK1/2 regulates ANG II-dependent cell proliferation via cytoplasmic activation of RSK2 and nuclear activation of elk1. Am J Physiol Cell Physiol 291:C1308-17
Frenzel, Kristen; Wallace, Tiffany A; McDoom, Issam et al. (2006) A functional Jak2 tyrosine kinase domain is essential for mouse development. Exp Cell Res 312:2735-44
Godeny, Michael D; Sayeski, Peter P (2006) ANG II-induced cell proliferation is dually mediated by c-Src/Yes/Fyn-regulated ERK1/2 activation in the cytoplasm and PKCzeta-controlled ERK1/2 activity within the nucleus. Am J Physiol Cell Physiol 291:C1297-307
Wallace, Tiffany A; Xia, Shen-Ling; Sayeski, Peter P (2005) Jak2 tyrosine kinase prevents angiotensin II-mediated inositol 1,4,5 trisphosphate receptor degradation. Vascul Pharmacol 43:336-45
Sandberg, Eric M; Ma, Xianyue; He, Kai et al. (2005) Identification of 1,2,3,4,5,6-hexabromocyclohexane as a small molecule inhibitor of jak2 tyrosine kinase autophosphorylation [correction of autophophorylation]. J Med Chem 48:2526-33
Sandberg, Eric M; Ma, Xianyue; VonDerLinden, Dannielle et al. (2004) Jak2 tyrosine kinase mediates angiotensin II-dependent inactivation of ERK2 via induction of mitogen-activated protein kinase phosphatase 1. J Biol Chem 279:1956-67

Showing the most recent 10 out of 16 publications