The IL-2 receptor promotes proliferation, bcl-2 and bcl-x induction, but not cell viability through the adapter molecule Shc.
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 beta-chain of this receptor (IL-2Rbeta) 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-2Rbeta/Shc fusion protein, in which Shc was covalently tethered to a truncated version of IL-2Rbeta 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.
Lord
J D
JD
Virginia Mason Research Center, Seattle, WA 98101, USA.
McIntosh
B C
BC
Greenberg
P D
PD
Nelson
B H
BH
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D004261:DNA Replication; D005786:Gene Expression Regulation / Q000502:physiology*; D019254:Genes, bcl-2; D016259:Genes, myc; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*; D014162:Transfection; D051020:bcl-X Protein
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C494812:Bcl2l1 protein, mouse; D007376:Interleukin-2; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D051020:bcl-X Protein; D019000:Phosphotyrosine