Interactions of CBL with BCR-ABL and CRKL in BCR-ABL-transformed myeloid cells.
The Philadelphia chromosome, detected in virtually all cases of chronic myelogenous leukemia (CML), is formed by a reciprocal translocation between chromosomes 9 and 22 that fuses BCR-encoded sequences upstream of exon 2 of c-ABL. The BCR-ABL fusion creates a gene whose protein product, p210BCR-ABL, has been implicated as the cause of the disease. Although ABL kinase activity has been shown to be required for the transforming abilities of BCR-ABL and numerous substrates of the BCR-ABL tyrosine kinase have been identified, the requirement of most of these substrates for the transforming function of BCR-ABL is unknown. In this study we mapped a direct binding site of the c-CBL proto-oncogene to the SH2 domain of BCR-ABL. This interaction only occurs under conditions where c-CBL is tyrosine-phosphorylated. Despite the direct interaction of c-CBL with the SH2 domain of BCR-ABL, deletion of the SH2 domain of BCR-ABL did not result in an alteration in the complex formation of BCR-ABL and c-CBL, suggesting that another site of direct interaction between c-CBL and BCR-ABL exists or that another protein mediates an indirect interaction of c-CBL and BCR-ABL. Since CRKL, an SH2, SH3 domain-containing adapter protein is known to bind directly to BCR-ABL and also binds to tyrosine-phosphorylated c-CBL, the ability of CRKL to mediate a complex between c-CBL and BCR-ABL was examined.
Bhat
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A
Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Kolibaba
K
K
Oda
T
T
Ohno-Jones
S
S
Heaney
C
C
Druker
B J
BJ
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D002461:Cell Line, Transformed; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D016044:Fusion Proteins, bcr-abl; C067419:CBL protein, human