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ヒト白血病癌遺伝子BCR-ABL活性化におけるBCRの役割：金　佳虎、渋谷正史、丸　義朗（医科研・細胞遺伝）

Effect of BCR sequences on the activation of the BCR-ABL oncogene of Philadelphia chromosome : Yoshitora KIN, Masabumi SHIBUYA, Yoshiro MARU (Dept.of Genetics, Inst.Med.Sci., Univ.of Tokyo)

The chimeric BCR-ABL oncogene causes human leukemias and the translocated BCR sequences appear to play an essential role in the activation of ABL.The BCR sequences retained in BCR-ABL include the amino-terminal oligomerization domain (region I),the SH2-binding domain (region II),and the Dbl-homology domain (region III). We and others previously reported that all the biological activities are dependent on the region I and that tyrosine kinases like Fes, Hck,and ABL phosphorylates the tyrosine residue 177 (Y177) in the region II, which results in the recruitment of the Ras activator Grb-2/SOS complex.
Here we show that the region II with the Y177F mutation in the absence of the region I can be tyrosine- phosphorylated in vivo by BCR-ABL and bind to the ABL SH2 domain in vitro more efficiently than that without tyrosine phosphorylations.A BCR-ABL mutant lacking the region II is unable to transform Rat1 fibroblasts. Interestingly, this defect is partially rescued by the additional deletion of the SH3 domain. Given the fact that the recently identified ABL SH3 domain-binding inhibitory protein AAP1 binds to ABL but not BCR-ABL,our data supports the proposed model in which intra or intermolecular binding between the SH2-binding domain of BCR and the ABL SH2 domain abrogates the ABL inhibitory effect mediated by the adjacent SH3 domain.
We also found that BCR lacking the region II could be tyrosine-phosphorylated in vivo by BCR-ABL, and that the region III when expressed in the form of GST fusion protein was tyrosine-phosphorylated in vitro by BCR-ABL. The region III is tought to be unnecessary for the BCR-ABL activation. However, this region is homologous to the catalytic domain of GDP-GTP exchangers like Dbl and Vav, and Vav was recently shown to be activated by tyrosine phosphorylation. We will further discuss about biological functions of BCR-ABL carrying mutations in the region III.