Bcr-Abl
The ABL protein physiologically shuttles between the nucleus and the cytoplasm; however, when fused to BCR, the oncoprotein loses this property and is mainly retained within the cytoplasm, where it interacts with the majority of proteins involved in the oncogenic pathway. ABL tyrosine kinase activity is constitutively activated by the juxtaposition of BCR, thus favoring dimerization or tetramerization and subsequent autophosphorylation. This increases the number of the phosphotyrosine residues on BCR-ABL and, as a consequence, the binding sites for the SH2 domains of other proteins. Abnormal interactions between the BCR-ABL oncoprotein and other cytoplasmic molecules lead to the disruption of key cellular processes.
Examples include the perturbation of the Ras–mitogen-activated protein kinase (MAPK) leading to increased proliferation, the Janus-activated kinase (JAK)–STAT pathway leading to impaired transcriptional activity, and the phosphoinositide 3-kinase (PI3K)/AKT pathway resulting in increased apoptosis. The aminoterminal BCR-encoded sequences of BCR-ABL contain a tyrosine-phosphorylated site that binds the SH2 domain of the adaptor protein GRB2. It is now evident that the phosphorylation of BCR Tyr177 is essential for BCR-ABL– mediated leukemogenesis, and its mutation largely abolishes GRB2 binding and diminishes BCR-ABL–induced Ras activation. Aberrant tyrosine kinase activity plays a critical role in many hematologic disorders, including chronic myeloid leukemia characterized by the constitutive activity of BCR-ABL. ABL therefore represents a crucial target for new therapeutic strategies.
References
1.Cilloni D,et al. Clin Cancer Res. 2012 Feb 15;18(4):930-7.
Examples include the perturbation of the Ras–mitogen-activated protein kinase (MAPK) leading to increased proliferation, the Janus-activated kinase (JAK)–STAT pathway leading to impaired transcriptional activity, and the phosphoinositide 3-kinase (PI3K)/AKT pathway resulting in increased apoptosis. The aminoterminal BCR-encoded sequences of BCR-ABL contain a tyrosine-phosphorylated site that binds the SH2 domain of the adaptor protein GRB2. It is now evident that the phosphorylation of BCR Tyr177 is essential for BCR-ABL– mediated leukemogenesis, and its mutation largely abolishes GRB2 binding and diminishes BCR-ABL–induced Ras activation. Aberrant tyrosine kinase activity plays a critical role in many hematologic disorders, including chronic myeloid leukemia characterized by the constitutive activity of BCR-ABL. ABL therefore represents a crucial target for new therapeutic strategies.
References
1.Cilloni D,et al. Clin Cancer Res. 2012 Feb 15;18(4):930-7.
Tyrosine Kinase
Bcr-Abl
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