Cooperation and selectivity of the two Grb2 binding sites of p52Shc in T-cell antigen receptor signaling to Ras family GTPases and Myc-dependent survival

Laura Patrussi, Maria Teresa Savino, Michela Pellegrini, Silvia Rossi Paccani, Enrica Migliaccio, Simon Plyte, Luisa Lanfrancone, Pier Giuseppe Pelicci, Cosima T. Baldari

Research output: Contribution to journalArticle

Abstract

Shc proteins participate in a variety of processes regulating cell proliferation, survival and apoptosis. The two ubiquitously expressed isoforms, p52Shc/p46Shc, couple tyrosine kinase receptors to Ras by recruiting Grb2/Sos complexes to a membrane-proximal localization. Tyrosine residues 239/240 and 317 become phosphorylated following receptor engagement and, as such, form two Grb2 binding sites, which have been proposed to be differentially coupled to Myc-dependent survival and to fos-dependent proliferation, respectively. Here, we have addressed the individual function of YY239/240 and Y317 in T-cell antigen receptor (TCR) signaling. We show that p52Shc is phosphorylated on both YY239/240 and Y317 following TCR engagement. Mutation of either YY239/ 240 or Y317 results in impaired interaction with Grb2 and inhibition of Ras/MAP kinase activation and CD69 induction, supporting a role for both Grb2 binding sites in this function. Substitution of either YY239/240 or Y317 also results in a defective activation of Rac and the coupled stress kinases JNK and p38. Furthermore, mutation of Y317 or, to a larger extent, of YY239/240, results in increased activation-induced cell death, which in cells expressing the FF239/240 mutant is accompanied by impaired TCR-dependent c-myc transcription. The data underline a pleiotropic and nonredundant role of Shc, mediated by both YY239/240 and Y317, in T-cell activation and survival.

Original languageEnglish
Pages (from-to)2218-2228
Number of pages11
JournalOncogene
Volume24
Issue number13
DOIs
Publication statusPublished - Mar 24 2005

Keywords

  • MAP kinases
  • Rac
  • Stress-activated kinases
  • T-cell activation
  • T-cell survival
  • TCR signaling

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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