Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma

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E Peles1, R B Levy, E Or

  • 1Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.

The EMBO Journal
|August 1, 1991
PubMed

Insights

The neu/HER2 proto-oncogene, when oncogenically activated, leads to constitutive phosphorylation of the neu protein and increased tyrosine phosphorylation of phospholipase C gamma (PLC gamma). This suggests PLC gamma activation is key to neu/HER2-mediated cellular transformation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The neu/HER2 proto-oncogene encodes a transmembrane tyrosine kinase.
  • Oncogenic activation of neu/HER2 can occur through mutation, truncation, or overexpression.
  • These alterations lead to constitutive activation of the receptor.

Purpose of the Study:

  • To investigate the downstream signaling events following oncogenic activation of the neu/HER2 receptor.
  • To determine the role of phospholipase C gamma (PLC gamma) in neu/HER2-mediated cellular transformation.

Main Methods:

  • Analysis of neu/HER2 protein phosphorylation status.
  • Assessment of PLC gamma tyrosine phosphorylation.
  • Co-immunoprecipitation assays to study protein interactions.
  • Use of kinase-defective mutants and chimeric receptors to probe functional interactions.

Main Results:

  • All oncogenic activation modes of neu/HER2 resulted in constitutive neu protein phosphorylation.
  • Increased tyrosine phosphorylation of PLC gamma was observed in transforming neu/HER2 variants.
  • Transforming neu/HER2 proteins, but not the normal product, co-immunoprecipitated with PLC gamma.
  • A kinase-defective neu mutant failed to induce PLC gamma tyrosine phosphorylation and association.
  • A chimeric receptor demonstrated ligand-dependent neu-PLC gamma interaction and PLC gamma modification.

Conclusions:

  • The neu/HER2 kinase directly interacts with and phosphorylates PLC gamma.
  • Activation of PLC gamma is a critical step in the cellular transformation process mediated by neu/HER2.
  • This study elucidates a key signaling pathway involved in neu/HER2-driven oncogenesis.

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