Opposite effects of the p52(shc)/p46(shc) and p66(shc) splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway

Enrica Migliaccio, Simonetta Mele, Anna E. Salcini, Giuliana Pelicci, K. M V Lai, Giulio Superti-Furga, Tony Pawson, Pier Paolo Di Fiore, Luisa Lanfrancone, Pier Giuseppe Pelicci

Research output: Contribution to journalArticle

Abstract

Shc proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to Ras. The p46shc and p52shc isoforms share a C-terminal SH2 domain, a proline- and glycine-rich region (collagen homologous region 1; CH1) and a N-terminal PTB domain. We have isolated cDNAs encoding for a third Shc isoform, p66shc. The predicted amino acid sequence of p66shc overlaps that of p52shc and contains a unique N-terminal region which is also rich in glycines and prolines (CH2). p52shc/p46shc is found in every cell type with invariant reciprocal relationship, whereas p66shc expression varies from cell type to cell type. p66shc differs from p52shc/p46shc in its inability to transform mouse fibroblasts in vitro. Like p52shc/p46shc, p66shc is tyrosine-phosphorylated upon epidermal growth factor (EGF) stimulation, binds to activated EGF receptors (EGFRs) and forms stable complexes with Grb2. However, unlike p52shc/p46shc it does not increase EGF activation of MAP kinases, but inhibits fos promoter activation. The isolated CH2 domain retains the inhibitory effect of p66shc on the fos promoter. p52shc/p46shc and p66shc, therefore, appear to exert different effects on the EGFR-MAP kinase and other signalling pathways that control fos promoter activity. Regulation of p66shc expression might, therefore, influence the cellular response to growth factors.

Original languageEnglish
Pages (from-to)706-716
Number of pages11
JournalEMBO Journal
Volume16
Issue number4
DOIs
Publication statusPublished - Feb 17 1997

Keywords

  • fos
  • p46(shc)
  • p52(shc)
  • p66(shc)
  • Phosphorylation
  • SH2 proteins

ASJC Scopus subject areas

  • Cell Biology
  • Genetics

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