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

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.