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Opposite effects of the p52 shc /p46 shc and p66 shc splicing isoforms on the EGF receptor–MAP kinase–fos signalling pathway
Author(s) -
Migliaccio Enrica,
Mele Simonetta,
Salcini Anna E.,
Pelicci Giuliana,
Lai KaMan Venus,
SupertiFurga Giulio,
Pawson Tony,
Di Fiore Pier Paolo,
Lanfrancone Luisa,
Pelicci Pier Giuseppe
Publication year - 1997
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/16.4.706
Subject(s) - biology , grb2 , gene isoform , epidermal growth factor , microbiology and biotechnology , alternative splicing , signal transduction , tyrosine kinase , receptor tyrosine kinase , kinase , tyrosine , mitogen activated protein kinase , phosphorylation , receptor , biochemistry , gene
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.