Sequences within the first exon of BCR inhibit the activated tyrosine kinases of c-Abl and the Bcr-Abl oncoprotein.
The Bcr-Abl oncoprotein is the primary causative factor in Philadelphia chromosome-associated leukemias. The activated tyrosine kinase of the Bcr-Abl oncoprotein is the primary driving force behind its oncogenic activity. We report here that a deleted form of Bcr [Bcr(64-413)], encompassing the Abl SH2 binding domains of Bcr, reduced the phosphotyrosine content of c-Abl and Bcr-Abl within cells and inhibited Bcr-Abl autophosphorylation activity in vitro. Similarly, a Bcr peptide phosphorylated on Ser-354 blocked the c-Abl and Bcr-Abl kinases in vitro, whereas the same peptide phosphorylated on Tyr-360 was not inhibitory. Bcr(64-413) was also resistant to tyrosine phosphorylation by either activated c-Abl or Bcr-Abl. Importantly, Bcr(64-413) interfered with the growth of Bcr-Abl-expressing cell lines. Our findings indicate that the Abl SH2 binding domain of Bcr in the phosphoserine form inhibits the Bcr-Abl oncoprotein but that tyrosine phosphorylation of this domain of Bcr reverses its inhibitory effects on Bcr-Abl. These results raise interesting questions about a possible role of Bcr or a Bcr-related molecule in modulating the activity of the Bcr-Abl oncoprotein and c-Abl itself.
Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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J
Liu
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Y
Wu
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RB
Arlinghaus
D000818:Animals; D019556:COS Cells; D004789:Enzyme Activation / Q000235:genetics; D005091:Exons / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D051562:Proto-Oncogene Proteins c-bcr; D018909:src Homology Domains
D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D051562:Proto-Oncogene Proteins c-bcr