HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 276, Issue 21, 17815-17822, May 25, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/21/17815    most recent M011405200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tibbles, H. E. Articles by Uckun, F. M. Search for Related Content PubMed PubMed Citation Articles by Tibbles, H. E. Articles by Uckun, F. M. Social Bookmarking                      What's this?

Role of a JAK3-dependent Biochemical Signaling Pathway in Platelet Activation and Aggregation^*

Heather E. Tibbles^§¶, Alexei Vassilev^¶, Heather Wendorf, Dawn Schonhoff^**, Dan Zhu^¶, David Lorenz^¶**, Barbara Waurzyniak, Xing-Ping Liu, and Fatih M. Uckun^**§§

From the  Parker Hughes Cancer Center, the Departments of ^§ Hematology, ^¶ Biochemistry,  Chemistry, and  Experimental Pathology, and the ^** Discovery Program, Parker Hughes Institute, St. Paul, Minnesota, 55113

Here we provide experimental evidence that identifies JAK3 as one of the regulators of platelet function. Treatment of platelets with thrombin induced tyrosine phosphorylation of the JAK3 target substrates STAT1 and STAT3. Platelets from JAK3-deficient mice displayed a decrease in tyrosine phosphorylation of STAT1 and STAT3. In accordance with these data, pretreatment of human platelets with the JAK3 inhibitor WHI-P131 markedly decreased the base-line enzymatic activity of constitutively active JAK3 and abolished the thrombin-induced tyrosine phosphorylation of STAT1 and STAT3. Following thrombin stimulation, WHI-P131-treated platelets did not undergo shape changes indicative of activation such as pseudopod formation. WHI-P131 inhibited thrombin-induced degranulation/serotonin release as well as platelet aggregation. Highly effective platelet inhibitory plasma concentrations of WHI-P131 were achieved in mice without toxicity. WHI-P131 prolonged the bleeding time of mice in a dose-dependent manner and improved event-free survival in a mouse model of thromboplastin-induced generalized and invariably fatal thromboembolism. To our knowledge, WHI-P131 is the first anti-thrombotic agent that prevents platelet aggregation by inhibiting JAK3.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				J. Fang, K. Hodivala-Dilke, B. D. Johnson, L. M. Du, R. O. Hynes, G. C. White II, and D. A. Wilcox Therapeutic expression of the platelet-specific integrin, {alpha}IIb{beta}3, in a murine model for Glanzmann thrombasthenia Blood, October 15, 2005; 106(8): 2671 - 2679. [Abstract] [Full Text] [PDF]

				Y. Li, W. Zhi, P. Wareski, and N.-p. Weng IL-15 Activates Telomerase and Minimizes Telomere Loss and May Preserve the Replicative Life Span of Memory CD8+ T Cells In Vitro J. Immunol., April 1, 2005; 174(7): 4019 - 4024. [Abstract] [Full Text] [PDF]

				G. J. Bhat, T. Samikkannu, J. J. Thomas, and T. J. Thekkumkara {alpha}-Thrombin Rapidly Induces Tyrosine Phosphorylation of a Novel, 74-78-kDa Stress Response Protein(s) in Lung Fibroblast Cells J. Biol. Chem., November 19, 2004; 279(47): 48915 - 48922. [Abstract] [Full Text] [PDF]

				T. Wiedmer, J. Zhao, L. Li, Q. Zhou, A. Hevener, J. M. Olefsky, L. K. Curtiss, and P. J. Sims Adiposity, dyslipidemia, and insulin resistance in mice with targeted deletion of phospholipid scramblase 3 (PLSCR3) PNAS, September 7, 2004; 101(36): 13296 - 13301. [Abstract] [Full Text] [PDF]

				E. Goleva, K. O. Kisich, and D. Y. M. Leung A Role for STAT5 in the Pathogenesis of IL-2-Induced Glucocorticoid Resistance J. Immunol., November 15, 2002; 169(10): 5934 - 5940. [Abstract] [Full Text] [PDF]

				Q. Zhou, J. Zhao, T. Wiedmer, and P. J. Sims Normal hemostasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1 Blood, May 13, 2002; 99(11): 4030 - 4038. [Abstract] [Full Text] [PDF]

				F. M. Uckun, J. Thoen, H. Chen, E. Sudbeck, C. Mao, R. Malaviya, X.-P. Liu, and C.-L. Chen CYP1A-Mediated Metabolism of the Janus Kinase-3 Inhibitor 4-(4'-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline: Structural Basis for Inactivation by Regioselective O-Demethylation Drug Metab. Dispos., January 1, 2002; 30(1): 74 - 85. [Abstract] [Full Text] [PDF]