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.
|Titolo:||Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway|
|Parole Chiave:||3T3 Cells; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Receptor, Epidermal Growth Factor; Enzyme Activation; RNA Splicing; Humans; Epidermal Growth Factor; Tyrosine; Mice; Amino Acid Sequence; Adaptor Proteins, Vesicular Transport; Cloning, Molecular; DNA, Complementary; Shc Signaling Adaptor Proteins; Promoter Regions, Genetic; Phosphorylation; Adaptor Proteins, Signal Transducing; GRB2 Adaptor Protein; Molecular Sequence Data; Proteins; Genes, fos; Signal Transduction; Cell Transformation, Neoplastic|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||17-feb-1997|
|Digital Object Identifier (DOI):||10.1093/emboj/16.4.706|
|Appare nelle tipologie:||01 - Articolo su periodico|