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Coupling of the c-Cbl protooncogene product to ErbB-1/EGF-receptor but not to other ErbB proteins.

The ErbB family of transmembrane tyrosine kinases includes the receptor for EGF (ErbB-1), two receptors for NDF/heregulin (ErbB-3 and ErbB-4) and an orphan receptor (ErbB-2). In order to examine the possibility that distinct signal transduction pathways are coupled to each ErbB protein, we examined the interaction of individual ligand-stimulated receptors with the c-Cbl protein, a protooncogene-encoded signaling molecule previously identified in hematopoietic cells. We report that c-Cbl undergoes rapid and sustained phosphorylation on tyrosine residues upon stimulation of fibroblast and epithelial cell lines with ligands of ErbB-1. By contrast, activation of either ErbB-3 or ErbB-4 by NDF did not affect tyrosine phosphorylation of c-Cbl. Likewise, activation of a chimeric ligand-stimulatable ErbB-2 by a heterologous ligand was ineffective. Despite rapidity of the EGF effect, we observed no association of c-Cbl with activated ErbB-1, implying that the interaction is indirect. Our in vitro experiments suggest that a candidate mediator of the interaction is the Grb-2/Ash adaptor protein, which is constitutively bound to c-Cbl. These results indicate that different ErbB proteins can couple to distinct signaling pathways, and therefore their physiological functions are probably non-redundant.

Pubmed ID: 8649804


  • Levkowitz G
  • Klapper LN
  • Tzahar E
  • Freywald A
  • Sela M
  • Yarden Y



Publication Data

March 7, 1996

Associated Grants

  • Agency: NCI NIH HHS, Id: CA51712

Mesh Terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Humans
  • Ligands
  • Phosphorylation
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-cbl
  • Rats
  • Receptor, Epidermal Growth Factor
  • Receptor, ErbB-3
  • Receptor, ErbB-4
  • Signal Transduction
  • Ubiquitin-Protein Ligases