Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells.

Lyn kinase functions as a regulator of imatinib sensitivity in chronic myelogenous leukemia (CML) cells through an unknown mechanism. In patients who fail imatinib therapy but have no detectable BCR-ABL kinase mutation, we detected persistently activated Lyn kinase. In imatinib-resistant CML cells and patients, Lyn activation is BCR-ABL independent, it ...
is complexed with the Gab2 and c-Cbl adapter/scaffold proteins, and it mediates persistent Gab2 and BCR-ABL tyrosine phosphorylation in the presence or absence of imatinib. Lyn silencing or inhibition is necessary to suppress Gab2 and BCR-ABL phosphorylation and to recover imatinib activity. Lyn also negatively regulates c-Cbl stability, whereas c-Cbl tyrosine phosphorylation is mediated by BCR-ABL. These results suggest that Lyn exists as a component of the BCR-ABL signaling complex and, in cells with high Lyn expression or activation, BCR-ABL kinase inhibition alone (imatinib) is not sufficient to fully disengage BCR-ABL-mediated signaling and suggests that BCR-ABL and Lyn kinase inhibition are needed to prevent or treat this form of imatinib resistance.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Drug Resistance, Neoplasm, Enzyme Activation, Fusion Proteins, bcr-abl, Gene Silencing, Humans, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Multiprotein Complexes, Mutation, Phosphorylation, Piperazines, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-cbl, Pyrimidines, Signal Transduction, src-Family Kinases
Blood
Date: Apr. 01, 2008
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