Evidence for a role for the phosphotyrosine-binding domain of Shc in interleukin 2 signaling.

Ravichandran KS, Igras V, Shoelson SE, Fesik SW, Burakoff SJ
Proc Natl Acad Sci U S A. 1996 93 (11): 5275-80

PMID: 8643566 · PMCID: PMC39235 · DOI:10.1073/pnas.93.11.5275

Stimulation via the T-cell growth factor interleukin 2 (IL-2) leads to tyrosine phosphorylation of Shc, the interaction of Shc with Grb2, and the Ras GTP/GDP exchange factor, mSOS. Shc also coprecipitates with the IL-2 receptor (IL-2R), and therefore, may link IL-2R to Ras activation. We have further characterized the Shc-IL-2R interaction and have made the following observations. (i) Among the two phosphotyrosine-interaction domains present in Shc, the phosphotyrosine-binding (PTB) domain, rather than its SH2 domain, interacts with the tyrosine-phosphorylated IL-2R beta chain. Moreover, the Shc-PTB domain binds a phosphopeptide derived from the IL-2R beta chain (corresponding to residues surrounding Y338, SCFTNQGpYFF) with high affinity. (ii) In vivo, mutant IL-2R beta chains lacking the acidic region of IL-2Rbeta (which contains Y338) fail to phosphorylate Shc. Furthermore, when wild type or mutant Shc proteins that lack the PTB domain were expressed in the IL-2-dependent CTLL-20 cell line, an intact Shc-PTB domain was required for Shc phosphorylation by the IL-2R, which provides further support for a Shc-PTB-IL-2R interaction in vivo. (iii) PTB and SH2 domains of Shc associate with different proteins in IL-2- and T-cell-receptor-stimulated lysates, suggesting that Shc, through the concurrent use of its two different phosphotyrosine-binding domains, could assemble multiple protein complexes. Taken together, our in vivo and in vitro observations suggest that the PTB domain of Shc interacts with Y338 of the IL-2R and provide evidence for a functional role for the Shc-PTB domain in IL-2 signaling.

MeSH Terms (19)

Amino Acid Sequence Animals Binding Sites Cell Line Humans Hybridomas Interleukin-2 Mice Molecular Sequence Data Phosphotyrosine Receptors, Interleukin-2 Recombinant Fusion Proteins Recombinant Proteins Sequence Tagged Sites Signal Transduction src Homology Domains T-Lymphocytes T-Lymphocytes, Cytotoxic Transfection

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