An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias

EMBO J. 1993 Apr;12(4):1533-46.

Abstract

In Philadelphia chromosome-positive human leukemias, which include chronic myelogenous leukemia and some acute lymphocytic leukemias, the c-abl proto-oncogene on chromosome 9 becomes fused to the bcr gene on chromosome 22, and Bcr-Abl fusion proteins are produced. The Bcr sequences activate the Abl tyrosine kinase which is required for the transforming function of Bcr-Abl. The Bcr sequences also enhance an F-actin-binding activity associated with c-Abl. Here, we show that binding of c-Abl and Bcr-Abl proteins to actin filaments in vivo and in vitro is mediated by an evolutionarily conserved domain at the C-terminal end of c-Abl. The c-Abl F-actin-binding domain contains a consensus motif found in several other actin-crosslinking proteins. Mutations in the consensus motif are shown to abolish binding to F-actin. Bcr-Abl proteins unable to associate with F-actin have a reduced ability to transform Rat-1 fibroblasts and to abrogate the requirement for interleukin-3 in the lymphoblastoid cell line Ba/F3. In transformed cells, Bcr-Abl induces a redistribution of F-actin into punctate, juxtanuclear aggregates. The binding to actin filaments has important implications for the pathogenic and physiological functions of the Bcr-Abl and c-Abl proteins.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Actin Cytoskeleton / ultrastructure
  • Amino Acid Sequence
  • Animals
  • Cell Division / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Chlorocebus aethiops
  • Consensus Sequence
  • DNA Mutational Analysis
  • Fluorescent Antibody Technique
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • In Vitro Techniques
  • Interleukin-3 / pharmacology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Mice
  • Microfilament Proteins / metabolism*
  • Molecular Sequence Data
  • Protein-Tyrosine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-abl / metabolism
  • Proto-Oncogene Proteins c-bcr
  • Rats
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Structure-Activity Relationship

Substances

  • Interleukin-3
  • Microfilament Proteins
  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Proto-Oncogene Proteins c-abl
  • BCR protein, human
  • Bcr protein, mouse
  • Proto-Oncogene Proteins c-bcr