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,
,,§
*
Virginia Mason Research Center, Seattle, WA 98101;
Fred Hutchinson Cancer Research Center, Seattle, WA 98104; and Departments of
Immunology and
§
Medicine, University of Washington, Seattle, WA 98195
IL-2, the principal mitogenic factor for activated T cells, delivers a proliferative signal through ligation of the heterotrimeric IL-2R. This proliferative signal is critically dependent upon cytoplasmic tyrosines on the ß-chain of this receptor (IL-2Rß) becoming phosphorylated in response to ligand. We found that at least one of these tyrosines (Y338) also mediates cell survival and induction of bcl-2, bcl-x, and c-myc in the murine T cell line CTLL-2. Since the adapter molecule Shc binds to phosphorylated Y338, the specific contribution of Shc to these events was evaluated. An IL-2Rß/Shc fusion protein, in which Shc was covalently tethered to a truncated version of IL-2Rß lacking all cytoplasmic tyrosines, revealed a robust proliferative signal mediated through Shc. This Shc-mediated signal induced expression of c-myc as well as the antiapoptotic genes bcl-2 and bcl-x with normal magnitude and kinetics. Nonetheless, signals from this fusion protein failed to sustain the long-term viability of CTLL-2 cells. Thus, induction of bcl family genes and delivery of a competent proliferative signal are not sufficient to promote cell survival and mediate the antiapoptotic effects associated with a complete IL-2 signal.
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