Anti-apoptotic Signaling by the Interleukin-2 Receptor Reveals a Function for Cytoplasmic Tyrosine Residues within the Common γ (γc) Receptor Subunit*
- From the ‡Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263 and the Departments of §Oral Biology and ¶Microbiology, State University of New York at Buffalo, Buffalo, New York 14214
Abstract
The interleukin-2 receptor (IL-2R) is composed of one affinity-modulating subunit (IL-2Rα) and two essential signaling subunits (IL-2Rβ and γc). Although most known signaling events are mediated through tyrosine residues located within IL-2Rβ, no functions have yet been ascribed to γc tyrosine residues. In this study, we describe a role for γc tyrosines in anti-apoptotic signal transduction. We have shown previously that a tyrosine-deficient IL-2Rβ chain paired with wild type γc stimulated enhancement of bcl-2 mRNA in IL-2-dependent T cells, but it was not determined which region of the IL-2R or which pathway was activated to direct this signaling response. Here we show that up-regulation of Bcl-2 by an IL-2R lacking IL-2Rβ tyrosine residues leads to increased cell survival after cytokine deprivation; strikingly, this survival signal does not occur in the absence of γc tyrosine residues. These γc-dependent signals are revealed only in the absence of IL-2Rβ tyrosines, indicating that the IL-2R engages at least two distinct signaling pathways to regulate apoptosis and Bcl-2 expression. Mechanistically, the γc-dependent signal requires activation of Janus kinases 1 and 3 and is sensitive to wortmannin, implicating phosphatidylinositol 3-kinase. Consistent with involvement of phosphatidylinositol 3-kinase, Akt can be activated via tyrosine residues on γc. Thus, γc mediates an anti-apoptotic signaling pathway through Akt which cooperates with signals from its partner chain, IL-2Rβ.
Footnotes
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↵* This work was supported by the Departments of Oral Biology and Microbiology at the State University of New York at Buffalo, National Institutes of Health Training Grant DE07034 (to M. J. L.), and Immune Deficiency Foundation and National Institutes of Health Grant AI49329 (to S. L. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‖ To whom correspondence should be addressed: Dept. of Oral Biology, 36 Foster Hall, 3435 Main St., Buffalo, NY 14214. E-mail: sgaffen@buffalo.edu.
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Published, JBC Papers in Press, January 12, 2003, DOI 10.1074/jbc.M209471200
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↵2 S. L. Gaffen, unpublished observations.
- Abbreviations:
- IL
-
interleukin
- EPO
-
erythropoietin
- EPOR
-
erythropoietin receptor
- FITC
-
fluorescein isothiocyanate
- GFP
-
green fluorescent protein
- IL-2R
-
interleukin-2 receptor
- JAK
-
Janus kinase
- MAPK
-
mitogen-activated protein kinase
- PI
-
propidium iodide
- PI3K
-
phosphatidylinositol 3-kinase
- STAT
-
signal transducer and activator of transcription
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- Received September 16, 2002.
- Revision received January 7, 2003.
- The American Society for Biochemistry and Molecular Biology, Inc.
