Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway

EMBO J. 1997 Feb 17;16(4):706-16. doi: 10.1093/emboj/16.4.706.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Transformation, Neoplastic
  • Cloning, Molecular
  • DNA, Complementary / genetics
  • Enzyme Activation
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism*
  • GRB2 Adaptor Protein
  • Genes, fos / genetics
  • Humans
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Proteins / genetics
  • Proteins / metabolism*
  • Proteins / physiology
  • RNA Splicing / physiology
  • Shc Signaling Adaptor Proteins
  • Signal Transduction / physiology*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Tyrosine / metabolism


  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • DNA, Complementary
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Proteins
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Tyrosine
  • Epidermal Growth Factor
  • ErbB Receptors
  • Calcium-Calmodulin-Dependent Protein Kinases

Associated data

  • GENBANK/U73377