OPPOSITE EFFECTS OF THE P52(SHC) P46(SHC) AND P66(SHC) SPLICING ISOFORMS ON THE EGF RECEPTOR-MAP KINASE-FOS SIGNALING PATHWAY/

Shc proteins are targets of activated tyrosine kinases and are implica ted in the transmission of activation signals to Ras. The p46shc and p 52shc isoforms share a C-terminal SH2 domain, a proline- and glycine-r ich region (collagen homologous region 1; CH1) and a N-terminal PTB do main. We have isolated cDNAs encoding for a third She isoform, p66shc. The predicted amino acid sequence of p66shc overlaps that of p52shc a nd contains a unique N-terminal region which is also rich in glycines and prolines (CH2), p52shc/p46shc is found in every cell type with inv ariant reciprocal relationship, whereas p66shc expression varies from cell type to cell type, p66shc differs from p52shc/p46shc in its inabi lity to transform mouse fibroblasts in vitro. Like p52shc/p46shc, p66s hc is tyrosine-phosphorylated upon epidermal growth factor (EGF) stimu lation, binds to activated EGF receptors (EGFRs) and forms stable comp lexes with Grb2. However, unlike p52shc/p46shc it does not increase EG F activation of MAP kinases, but inhibits fos promoter activation. The isolated CH2 domain retains the inhibitory effect of p66shc on the fo s promoter. p52shc/p46shc and p66shc, therefore, appear to exert diffe rent 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.