Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway

Lorri Puil, Jiaxin Liu, Gerald Gish, Geraldine Mbamalu, David Bowtell, Pier Giuseppe Pelicci, Ralph Arlinghaus, Tony Pawson

Research output: Contribution to journalArticle

Abstract

The cytosolic 185 and 210 kDa Bcr-Abl protein tyrosine kinases play important roles in the development of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (Ph+ ALL). p185 and p210 Bcr-Abl contain identical abl-encoded sequences juxtaposed to a variable number of bcr-derived amino acids. As the mitogenic and transforming activities of tyrosine kinases involve stimulation of the Ras pathway, we analyzed Bcr-Abl oncoproteins for interactions with cytoplasmic proteins that mediate Ras activation. Such polypeptides include Grb2, which comprises a single Src homology 2 (SH2) domain flanked by two SH3 domains, and the 66, 52 and 46 kDa Shc proteins which possess an SH2 domain in their carboxy-terminus. Grb2 associates with tyrosine phosphorylated proteins through its SH2 domain, and with the Ras guanine nucleotide releasing protein mSos1 through its SH3 domains. mSos1 stimulates conversion of the inactive GDP-bound form of Ras to the active GTP-bound state. In bcr-abl-transformed cells, Grb2 and mSos1 formed a physical complex with Bcr-Abl. In vitro, the Grb2 SH2 domain bound Bcr-Abl through recognition of a tyrosine phosphorylation site within the amino-terminal bcr-encoded sequence (p.Tyrl77-Val-Asn-Val), that is common to both Bcr-Abl proteins. These results suggest that autophosphorylation within the Bcr element of Bcr-Abl creates a direct physical link to Grb2-mSos1, and potentially to the Ras pathway, and thereby modifies the target specificity of the Abl tyrosine kinase. Bcr-Abl tyrosine kinases also phosphorylate Shc proteins on tyrosine, inducing the formation of an Shc-Grb2 complex that also has the potential to stimulate Ras. Bcr-Abl oncoproteins may therefore couple to the Ras pathway through the formation of multiple Grb2 complexes.

Original languageEnglish
Pages (from-to)764-773
Number of pages10
JournalEMBO Journal
Volume13
Issue number4
Publication statusPublished - Feb 15 1994

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Keywords

  • Bcr-Abl
  • Grb2
  • Leukemia
  • Ras
  • Sos

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Puil, L., Liu, J., Gish, G., Mbamalu, G., Bowtell, D., Pelicci, P. G., Arlinghaus, R., & Pawson, T. (1994). Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO Journal, 13(4), 764-773.