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Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia Arlinghaus RBOncogene 2002[Dec]; 21 (56): 8560-7The fusion of 5' parts of the BCR gene to the ABL gene at the second exon yields several forms of an oncogenic Bcr-Abl oncoprotein observed in several types of Philadelphia chromosome positive leukemia patients. The first exon of the BCR gene is a critical part of this fusion, as the coiled-coil domain at the amino terminal domain of the Bcr protein causes oligomerization of the Bcr-Abl oncoprotein forming tetramers, thereby activating the tyrosine kinase activity of the normally silent c-Abl protein. Another consequence of this Bcr-Abl fusion is the extensive autophosphorylation of the cis Bcr protein sequences on tyrosine residues. This review will summarize the effects of Bcr-Abl autophosphorylation on tyrosines as they relate to the oncogenic activity of Bcr-Abl, and as a means to inactivate the serine/threonine kinase activity of the Bcr protein. The review also discusses our findings that show that phosphoserine Bcr by means of a unique structure, binds to the Abl SH2 domain of the Bcr-Abl oncoprotein, and as a result this SH2 binding inhibits the oncogenic effects of the oncoprotein. Our results indicate that one effect of this binding is inhibition of the Bcr-Abl tyrosine kinase. Serine 354 of Bcr plays a major role in this inhibition. In the case of Bcr(64-413), serine 354 is required for the formation of the unique Bcr structure that binds to the Abl SH2 domain.|*Proto-Oncogene Proteins[MESH]|Amino Acid Sequence[MESH]|Animals[MESH]|Fusion Proteins, bcr-abl[MESH]|Gene Expression Regulation, Enzymologic/*physiology[MESH]|Gene Expression Regulation, Neoplastic/*physiology[MESH]|Humans[MESH]|Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/metabolism/pathology[MESH]|Mice[MESH]|Oncogene Proteins/*physiology[MESH]|Phosphorylation[MESH]|Protein-Tyrosine Kinases/chemistry/*genetics/metabolism[MESH]|Proto-Oncogene Proteins c-bcr[MESH]|Tyrosine/metabolism[MESH] |