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Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu.

Publication ,  Journal Article
Xie, Y; Pendergast, AM; Hung, MC
Published in: J Biol Chem
December 22, 1995

To clarify the role of the Shc-Grb2-Sos trimer in the oncogenic signaling of the point mutation-activated HER-2/neu receptor tyrosine kinase (named p185), we interfered with the protein-protein interactions in the Shc.Grb2.Sos complex by introducing Grb2 mutants with deletions in either amino- (delta N-Grb2) or carboxyl-(delta C-Grb2) terminal SH3 domains into B104-1-1 cells derived from NIH3T3 cells expressing the point mutation-activated HER-2/neu. We found that the transformed phenotypes of the B104-1-1 cells were largely reversed by the delta N-Grb2. The effect of the delta C-Grb2 was much weaker. Biochemical analysis showed that the delta N-Grb2 was able to associate Shc but not p185 or Sos, while the delta C-Grb2 bound to Shc, p185, and Sos. The p185-mediated Ras activation was severely inhibited by the delta N-Grb2 but not the delta C-Grb2. Taken together, these data demonstrate that interruption of the interaction between Shc and the endogenous Grb2 by the delta N-Grb2 impairs the oncogenic signaling of the activated p185, indicating that (i) the delta N-Grb2 functions as a strong dominant-negative mutant, and (ii) Shc/Grb2/Sos pathway plays a major role in mediating the oncogenic signal of the activated p185. Unlike the delta N-Grb2, delta C-Grb2 appears to be a relatively weak dominant-negative mutant, probably due to its ability to largely fulfill the biological functions of the wild-type Grb2.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 22, 1995

Volume

270

Issue

51

Start / End Page

30717 / 30724

Location

United States

Related Subject Headings

  • src Homology Domains
  • Transfection
  • Sequence Deletion
  • Recombinant Proteins
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Rats
  • Proteins
  • Point Mutation
  • Phenotype
 

Citation

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Xie, Y., Pendergast, A. M., & Hung, M. C. (1995). Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu. J Biol Chem, 270(51), 30717–30724. https://doi.org/10.1074/jbc.270.51.30717
Xie, Y., A. M. Pendergast, and M. C. Hung. “Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu.J Biol Chem 270, no. 51 (December 22, 1995): 30717–24. https://doi.org/10.1074/jbc.270.51.30717.
Xie, Y., et al. “Dominant-negative mutants of Grb2 induced reversal of the transformed phenotypes caused by the point mutation-activated rat HER-2/Neu.J Biol Chem, vol. 270, no. 51, Dec. 1995, pp. 30717–24. Pubmed, doi:10.1074/jbc.270.51.30717.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

December 22, 1995

Volume

270

Issue

51

Start / End Page

30717 / 30724

Location

United States

Related Subject Headings

  • src Homology Domains
  • Transfection
  • Sequence Deletion
  • Recombinant Proteins
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Rats
  • Proteins
  • Point Mutation
  • Phenotype