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

Gishizky ML, Cortez D, Pendergast AM
Proc Natl Acad Sci U S A. 1995 92 (24): 10889-93

PMID: 7479904 · PMCID: PMC40536 · DOI:10.1073/pnas.92.24.10889

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.

MeSH Terms (22)

Adaptor Proteins, Signal Transducing Animals Cell Differentiation Cell Division Cell Transformation, Neoplastic Fusion Proteins, bcr-abl GRB2 Adaptor Protein Humans Leukemia, Myelogenous, Chronic, BCR-ABL Positive Mice Mice, Nude Protein-Serine-Threonine Kinases Protein-Tyrosine Kinases Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-raf Proto-Oncogene Proteins p21(ras) Rats Signal Transduction src Homology Domains Structure-Activity Relationship Tumor Cells, Cultured

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