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BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein.

Publication ,  Journal Article
Pendergast, AM; Quilliam, LA; Cripe, LD; Bassing, CH; Dai, Z; Li, N; Batzer, A; Rabun, KM; Der, CJ; Schlessinger, J
Published in: Cell
October 8, 1993

BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph1)-positive human leukemias. Sequences within the first exon of BCR are required to activate the transforming potential of BCR-ABL. The SH2/SH3 domain-containing GRB-2 protein links tyrosine kinases to Ras signaling. We demonstrate that BCR-ABL exists in a complex with GRB-2 in vivo. Binding of GRB-2 to BCR-ABL is mediated by the direct interaction of the GRB-2 SH2 domain with a phosphorylated tyrosine, Y177, within the BCR first exon. The BCR-ABL-GRB-2 interaction is required for activation of the Ras signaling pathway. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation. The BCR-ABL (Y177F) mutant is unable to transform primary bone marrow cultures and is impaired in its ability to transform Rat1 fibroblasts. These findings implicate activation of Ras function as an important component in BCR-ABL-mediated transformation and demonstrate that GRB-2 not only functions in normal development and mitogenesis but also plays a role in oncogenesis.

Duke Scholars

Published In

Cell

ISSN

0092-8674

Publication Date

October 8, 1993

Volume

75

Issue

1

Start / End Page

175 / 185

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transcription, Genetic
  • Recombinant Fusion Proteins
  • Proto-Oncogenes
  • Proto-Oncogene Proteins c-bcr
  • Proto-Oncogene Proteins
  • Proteins
  • Protein-Tyrosine Kinases
  • Protein Binding
  • Promoter Regions, Genetic
 

Citation

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MLA
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Pendergast, A. M., Quilliam, L. A., Cripe, L. D., Bassing, C. H., Dai, Z., Li, N., … Schlessinger, J. (1993). BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell, 75(1), 175–185.
Pendergast, A. M., L. A. Quilliam, L. D. Cripe, C. H. Bassing, Z. Dai, N. Li, A. Batzer, K. M. Rabun, C. J. Der, and J. Schlessinger. “BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein.Cell 75, no. 1 (October 8, 1993): 175–85.
Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, et al. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell. 1993 Oct 8;75(1):175–85.
Pendergast, A. M., et al. “BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein.Cell, vol. 75, no. 1, Oct. 1993, pp. 175–85.
Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, Batzer A, Rabun KM, Der CJ, Schlessinger J. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell. 1993 Oct 8;75(1):175–185.
Journal cover image

Published In

Cell

ISSN

0092-8674

Publication Date

October 8, 1993

Volume

75

Issue

1

Start / End Page

175 / 185

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transcription, Genetic
  • Recombinant Fusion Proteins
  • Proto-Oncogenes
  • Proto-Oncogene Proteins c-bcr
  • Proto-Oncogene Proteins
  • Proteins
  • Protein-Tyrosine Kinases
  • Protein Binding
  • Promoter Regions, Genetic