This application outlines the research plan of Dr. Peter Sayeski concerning the role of Jak2 tyrosine kinase in cellular signaling and disease. Early studies of angiotensin II signal transduction mechanisms focused on the role of heterotrimeric G proteins as being key mediators of both the physiological and pathophysiological actions of angiotensin II. However, more recent studies have clearly established that tyrosine kinases such as Jak2 also mediate the physiological and pathophysiological actions of angiotensin II. Additionally, recent work has shown that a specific mutant form of Jak2, Jak2-V617F, is the cause of a large number of myeloproliferative blood disorders. The basis of the disease is that the mutation results in a constitutively active Jak2 kinase protein that is unresponsive to the negative feedback mechanisms that govern normal cell growth. Jak2 is a member of the Janus family of tyrosine kinases. It transduces cellular signals via its binding to cell surface receptors and subsequent tyrosine phosphorylation of substrates, such as the Signal Transducers and Activators of Transcription (STAT) proteins. Phosphorylated STAT proteins translocate into the nucleus were they modulate gene transcription. Thus, Jak2 acts as a key intermediate in linking ligand binding at the cell surface with changes in gene transcription within the nucleus. Recent studies have demonstrated that abnormal Jak2 kinase activity is linked to a host of human pathologies including heart disease, cancer and a variety of myeloproliferative and hematological disorders. The preliminary data in this proposal demonstrate that we have 1) identified a tyrosine residue within Jak2 that is critical for kinase function 2) defined a critical role for this residue in angiotensin II-mediated VSMC migration 3) identified two putative Jak2 tyrosine kinase inhibitors and 4) have developed a model whereby the affects of these inhibitors on Jak2 function can be ascertained, in vivo. Here, we propose a series of studies that will define the role of this tyrosine residue on overall Jak2 kinase function as well as characterize the efficacy of these two inhibitors to block Jak2 function in vitro and in vivo. Collectively, the results of these studies may help patients suffering from diseases that are caused by abnormal Jak2 kinase function.
Abnormal Jak2 tyrosine kinase function has been linked to a number of human diseases including cardiovascular disease, diabetes and numerous blood disorders. The studies outlined in this application will provide us with 1) a better understanding of how Jak2 works and 2) determine the how well two potential Jak2 inhibitors block Jak2 function in animals. Collectively, the results from these studies may one day improve the quality of life of patients who suffer from Jak2 related disorders.
|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|
|Gnanasambandan, K; Sayeski, P P (2011) A structure-function perspective of Jak2 mutations and implications for alternate drug design strategies: the road not taken. Curr Med Chem 18:4659-73|
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