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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-04-1251. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-04-1251v1 101/1/236    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jiang, K. Articles by Djeu, J. Y. Search for Related Content PubMed PubMed Citation Articles by Jiang, K. Articles by Djeu, J. Y. Related Collections Signal Transduction Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 January 2003, Vol. 101, No. 1, pp. 236-244 IMMUNOBIOLOGY Regulation of Akt-dependent cell survival by Syk and Rac Kun Jiang, Bin Zhong, Connie Ritchey, Danielle L. Gilvary, Elizabeth Hong-Geller, Sheng Wei, and Julie Y. Djeu From the Immunology Program, H. Lee Moffitt Cancer Center, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa; and Los Alamos National Laboratories, NM. Interleukin-2 (IL-2) prevents cell apoptosis and promotes survival, but the involved mechanisms have not been completely defined. Although phosphatidylinositide 3-kinase (PI 3-kinase) has been implicated in IL-2-mediated survival mechanisms, none of the 3 chains of the IL-2 receptor (IL-2R) expresses a binding site for PI 3-kinase. However, IL-2R does express a Syk-binding motif. By using an IL-2-dependent natural killer (NK) cell line, followed by validation of the results in fresh human NK cells, we identified Syk as a critical effector essential for IL-2-mediated prosurvival signaling in NK cells. Down-regulation of Syk by piceatannol treatment impaired NK cellular viability and induced prominent apoptosis as effectively as suppression of PI 3-kinase function by LY294002. Expression of kinase-deficient Syk or pretreatment with piceatannol markedly suppressed IL-2-stimulated activation of PI 3-kinase and Akt, demonstrating that Syk is upstream of PI 3-kinase and Akt. However, constitutively active PI 3-kinase reversed this loss of Akt function caused by kinase-deficient Syk or piceatannol. Thus, Syk appears to regulate PI 3-kinase, which controls Akt activity during IL-2 stimulation. More important, we observed Rac1 activation by IL-2 and found that it mediated PI 3-kinase activation of Akt. This conclusion came from experiments in which dominant-negative Rac1 significantly decreased IL-2-induced Akt activation, whereas constitutively active Rac1 reelevated Akt activity not only in Syk-impaired but also in PI 3-kinase-impaired NK cells. These results constitute the first report of a Syk  PI3K  Rac1  Akt signal cascade controlled by IL-2 that mediates NK cell survival. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. W. MacFarlane IV, T. Yamazaki, M. Fang, L. J. Sigal, T. Kurosaki, and K. S. Campbell Enhanced NK-cell development and function in BCAP-deficient mice Blood, July 1, 2008; 112(1): 131 - 140. [Abstract] [Full Text] [PDF] S. Luangdilok, C. Box, L. Patterson, W. Court, K. Harrington, L. Pitkin, P. Rhys-Evans, P. O-charoenrat, and S. 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