Protein Kinase D2 Mediates Activation of Nuclear Factor κB by Bcr-Abl in Bcr-Abl+ Human Myeloid Leukemia Cells

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Abstract
The Bcr-Abl tyrosine kinase activates various signaling pathways including nuclear factor κB that mediate proliferation, transformation, and apoptosis resistance in Bcr-Abl+ myeloid leukemia cells. Here we report that protein kinase (PK) D2, a serine threonine kinase of the PKD family, is a novel substrate of Bcr-Abl. PKD2 was found to be the major isoform of the PKD family expressed in chronic myeloid leukemia cells and is tyrosine phosphorylated by Bcr-Abl in its pleckstrin homology domain. A mutant that mimicks tyrosine phosphorylation of PKD2 in the pleckstrin homology domain activates nuclear factor κB independently of its catalytic activity. Furthermore, our data show that Bcr-Abl–induced activation of the nuclear factor κB cascade in LAMA84 cells is largely mediated by tyrosine-phosphorylated PKD2. These data present a novel mechanism of Bcr-Abl–induced nuclear factor κB activation in myeloid leukemia. Targeting PKD2 tyrosine phosphorylation, not its kinase activity, could be a novel therapeutic approach for the treatment of Bcr-Abl+ myeloid leukemia.