BCR sequences essential for transformation by the BCR-ABL oncogene bind to the ABL SH2 regulatory domain in a non-phosphotyrosine-dependent manner.
BCR-ABL is a chimeric oncogene implicated in the pathogenesis of Philadelphia chromosome-positive human leukemias. BCR first exon sequences specifically activate the tyrosine kinase and transforming potential of BCR-ABL. We have tested the hypothesis that activation of BCR-ABL may involve direct interaction between BCR sequences and the tyrosine kinase regulatory domains of ABL. Full-length c-BCR as well as BCR sequences retained in BCR-ABL bind specifically to the SH2 domain of ABL. The binding domain has been localized within the first exon of BCR and consists of at least two SH2-binding sites. This domain is essential for BCR-ABL-mediated transformation. Phosphoserine/phosphothreonine but not phosphotyrosine residues on BCR are required for interaction with the ABL SH2 domain. These findings extend the range of potential SH2-protein interactions in growth control pathways and suggest a function for SH2 domains in the activation of the BCR-ABL oncogene as well as a role for BCR in cellular signaling pathways.
Pendergast
A M
AM
Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90024-1570.
Muller
A J
AJ
Havlik
M H
MH
Maru
Y
Y
Witte
O N
ON
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005091:Exons; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D016313:Genes, abl; D014644:Genetic Variation; D006801:Humans; D007313:Insecta; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000235:genetics*; D009857:Oncogenes; D019000:Phosphotyrosine; D010957:Plasmids; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051562:Proto-Oncogene Proteins c-bcr; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives
D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr