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STAT5 Is Essential for Akt/p70S6 Kinase Activity during IL-2-Induced Lymphocyte Proliferation¹

Heather M. Lockyer^2,*, Eric Tran^2,*, and Brad H. Nelson^3,*,

^* British Columbia Cancer Agency, Trev and Joyce Deeley Research Centre, Victoria, Canada; and Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada

IL-2R activates two distinct signaling pathways mediated by the adaptor protein Shc and the transcription factor STAT5. Prior mutagenesis studies of the IL-2R have indicated that the Shc and STAT5 pathways are redundant in the ability to induce lymphocyte proliferation. Yet paradoxically, T cells from STAT5-deficient mice fail to proliferate in response to IL-2, suggesting that the Shc pathway is unable to promote mitogenesis in the genetic absence of STAT5. Here we show in the murine lymphocyte cell line Ba/F3 that low levels of STAT5 activity are essential for Shc signaling. In the absence of STAT5 activity, Shc was unable to sustain activation of the Akt/p70S6 kinase pathway or promote lymphocyte proliferation and viability. Restoring STAT5 activity via a heterologous receptor rescued Shc-induced Akt/p70S6 kinase activity and cell proliferation with kinetics consistent with a transcriptional mechanism. Thus, STAT5 appears to regulate the expression of one or more unidentified components of the Akt pathway. Our results not only explain the severe proliferative defect in STAT5-deficient T cells but also provide mechanistic insight into the oncogenic properties of STAT5 in various leukemias and lymphomas.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by National Institutes of Health Grant GM57931 and the British Columbia Cancer Foundation. E.T. was supported by a Canada Graduate Scholarship (CGS-M) from the National Sciences and Engineering Research Council of Canada.

² H.M.L. and E.T. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Brad H. Nelson, 2410 Lee Avenue, Victoria, British Columbia, Canada. E-mail address: bnelson{at}bccancer.bc.ca

⁴ Abbreviations used in this paper: PIP₃, phosphatidylinositol 3,4,5-triphosphate; PDK1, phosphoinositide-dependent kinase 1; caSTAT5, constitutively active mutant of STAT5; QPCR, quantitative PCR; wtSTAT5A, wild-type STAT5A.

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