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Mutant forms of growth factor-binding protein-2 reverse BCR-ABL-induced transformation.

Publication ,  Journal Article
Gishizky, ML; Cortez, D; Pendergast, AM
Published in: Proc Natl Acad Sci U S A
November 21, 1995

Growth factor-binding protein 2 (Grb2) is an adaptor protein that links tyrosine kinases to Ras. BCR-ABL is a tyrosine kinase oncoprotein that is implicated in the pathogenesis of Philadelphia chromosome (Ph1)-positive leukemias. Grb2 forms a complex with BCR-ABL and the nucleotide exchange factor Sos that leads to the activation of the Ras protooncogene. In this report we demonstrate that Grb2 mutant proteins lacking amino- or carboxyl-terminal src homology SH3 domains suppress BCR-ABL-induced Ras activation and reverse the oncogenic phenotype. The Grb2 SH3-deletion mutant proteins bind to BCR-ABL and do not impair tyrosine kinase activity. Expression of the Grb2 SH3-deletion mutant proteins in BCR-ABL-transformed Rat-1 fibroblasts and in the human Ph1-positive leukemic cell line K562 inhibits their ability to grow as foci in soft agar and form tumors in nude mice. Furthermore, expression of the Grb2 SH3-deletion mutants in K562 cells induced their differentiation. Because Ras plays an important role in signaling by receptor and nonreceptor tyrosine kinases, the use of interfering mutant Grb2 proteins may be applied to block the proliferation of other cancers that depend in part on activated tyrosine kinases for growth.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

November 21, 1995

Volume

92

Issue

24

Start / End Page

10889 / 10893

Location

United States

Related Subject Headings

  • src Homology Domains
  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Signal Transduction
  • Rats
  • Proto-Oncogene Proteins p21(ras)
  • Proto-Oncogene Proteins c-raf
  • Proto-Oncogene Proteins
  • Proteins
  • Protein-Tyrosine Kinases
 

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Gishizky, M. L., Cortez, D., & Pendergast, A. M. (1995). Mutant forms of growth factor-binding protein-2 reverse BCR-ABL-induced transformation. Proc Natl Acad Sci U S A, 92(24), 10889–10893. https://doi.org/10.1073/pnas.92.24.10889
Gishizky, M. L., D. Cortez, and A. M. Pendergast. “Mutant forms of growth factor-binding protein-2 reverse BCR-ABL-induced transformation.Proc Natl Acad Sci U S A 92, no. 24 (November 21, 1995): 10889–93. https://doi.org/10.1073/pnas.92.24.10889.
Gishizky ML, Cortez D, Pendergast AM. Mutant forms of growth factor-binding protein-2 reverse BCR-ABL-induced transformation. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):10889–93.
Gishizky, M. L., et al. “Mutant forms of growth factor-binding protein-2 reverse BCR-ABL-induced transformation.Proc Natl Acad Sci U S A, vol. 92, no. 24, Nov. 1995, pp. 10889–93. Pubmed, doi:10.1073/pnas.92.24.10889.
Gishizky ML, Cortez D, Pendergast AM. Mutant forms of growth factor-binding protein-2 reverse BCR-ABL-induced transformation. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):10889–10893.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

November 21, 1995

Volume

92

Issue

24

Start / End Page

10889 / 10893

Location

United States

Related Subject Headings

  • src Homology Domains
  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Signal Transduction
  • Rats
  • Proto-Oncogene Proteins p21(ras)
  • Proto-Oncogene Proteins c-raf
  • Proto-Oncogene Proteins
  • Proteins
  • Protein-Tyrosine Kinases