This application outlines the research and career planproposed by Dr. Peter P. Sayeski concerning the mechanisms by which the non-receptor tyrosine kinase, Jak2, binds the angiotensin II type AT1 receptor and subsequently mediates the angiotensin 11-dependent nuclear accumulation of Stat 1. 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 that end with increased vasoconstrictive and mitogenic growth responses. The pharmacological 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. Thus, defining the proximal biochemical and cellular events that allow Jak2 to bind the AT1 receptor and subsequently facilitate the translocation of Stat 1 into the nucleus where it modulates gene transcription, will greatly advance this concept. Furthermore, the results of these experiments will be of great interest to the signal transduction community as a whole, at it addresses the fundamental question of how cell surface receptors activate the JakI STAT signaling pathway. 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 the angiotensin TI-dependent nuclear accumulation of Stat 1. The research will be performed at the University of Florida, 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 Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067277-05
Application #
7014073
Study Section
Pathology A Study Section (PTHA)
Program Officer
Lin, Michael
Project Start
2002-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$284,162
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Baskin, Rebekah; Park, Sung O; Keser?, György M et al. (2014) The Jak2 small molecule inhibitor, G6, reduces the tumorigenic potential of T98G glioblastoma cells in vitro and in vivo. PLoS One 9:e105568
Jin, Xi; Zhao, Wanke; Kirabo, Annet et al. (2014) Elevated levels of mast cells are involved in pruritus associated with polycythemia vera in JAK2V617F transgenic mice. J Immunol 193:477-84
Park, Sung O; Wamsley, Heather L; Bae, Kyungmi et al. (2013) Conditional deletion of Jak2 reveals an essential role in hematopoiesis throughout mouse ontogeny: implications for Jak2 inhibition in humans. PLoS One 8:e59675
Gnanasambandan, Kavitha; Magis, Andrew T; Sayeski, Peter P (2012) A shift in the salt bridge interaction of residues D620 and E621 mediates the constitutive activation of Jak2-H538Q/K539L. Mol Cell Biochem 367:125-40
Kirabo, Annet; Park, Sung O; Wamsley, Heather L et al. (2012) The small molecule inhibitor G6 significantly reduces bone marrow fibrosis and the mutant burden in a mouse model of Jak2-mediated myelofibrosis. Am J Pathol 181:858-65
Baskin, Rebekah; Sayeski, Peter P (2012) Angiotensin II mediates cell survival through upregulation and activation of the serum and glucocorticoid inducible kinase 1. Cell Signal 24:435-42
Majumder, Anurima; Magis, Andrew T; Park, Sung O et al. (2012) A46, a benzothiophene-derived compound, suppresses Jak2-mediated pathologic cell growth. Exp Hematol 40:22-34
Baskin, Rebekah; Gali, Meghanath; Park, Sung O et al. (2012) Identification of novel SAR properties of the Jak2 small molecule inhibitor G6: significance of the para-hydroxyl orientation. Bioorg Med Chem Lett 22:1402-7
Kirabo, Annet; Embury, Jennifer; Kiss, Róbert et al. (2011) The stilbenoid tyrosine kinase inhibitor, G6, suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo. J Biol Chem 286:4280-91
Majumder, Anurima; Kirabo, Annet; Karrupiah, Kanchana et al. (2011) Cell death induced by the Jak2 inhibitor, G6, correlates with cleavage of vimentin filaments. Biochemistry 50:7774-86

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