The aminoterminal phosphotyrosine binding domain of Shc associates with ZAP-70 and mediates TCR dependent gene activation

Elisabetta Milia, M. Maddalena Di Somma, Fabiana Baldoni, Rita Chiari, Luisa Lanfrancone, Pier Giuseppe Pelicci, John L. Telford, Cosima T. Baldari

Research output: Contribution to journalArticle

Abstract

T-cell antigen receptor stimulation results in recruitment to the ζ chain and phosphorylation both of the syk family protein tyrosine kinase ZAP-70 and of the Shc adaptor protein, which transduces activating signals to Ras. Both ZAP-70 and Ras are required for T-cell activation. We have investigated the functional link between these two molecules in TCR signaling. Shc was found to associate with ZAP-70 in response to TCR triggering. This association was dependent on the presence of the aminoterminal phosphotyrosine binding (PTB) domain of Shc. The analysis of Shc binding to a potential PTB domain binding site on ZAP-70 confirmed the interaction of the Shc PTB domain with ZAP-70 and identified the ZAP-70 phosphotyrosine residue involved in this interaction. To test the role of the Shc PTB domain in transducing TCR derived signals we measured the effects of the isolated Shc PTB domain on the activation of the T-cell specific transcription factor NF-AT. The isolated Shc PTB domain was designed to compete non productively with endogenous Shc for binding to upstream tyrosine phosphorylated proteins and thus interfere with coupling to regulators of Ras activation. A significant inhibition of NF-AT activation by TCR triggering was observed, showing a functional involvement of Shc in TCR signaling through its PTB domain and suggesting an important role for Shc association with ZAP-70.

Original languageEnglish
Pages (from-to)767-775
Number of pages9
JournalOncogene
Volume13
Issue number4
Publication statusPublished - 1996

Keywords

  • PTB domain
  • Shc
  • T-cell
  • TCR
  • ZAP-70

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Milia, E., Di Somma, M. M., Baldoni, F., Chiari, R., Lanfrancone, L., Pelicci, P. G., Telford, J. L., & Baldari, C. T. (1996). The aminoterminal phosphotyrosine binding domain of Shc associates with ZAP-70 and mediates TCR dependent gene activation. Oncogene, 13(4), 767-775.