Protein kinase D2 mediates activation of nuclear factor kappaB by Bcr-Abl in Bcr-Abl+ human myeloid leukemia cells.

Abstract

The Bcr-Abl tyrosine kinase activates various signaling pathways including nuclear factor kappaB 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 kappaB independently of its catalytic activity. Furthermore, our data show that Bcr-Abl-induced activation of the nuclear factor kappaB cascade in LAMA84 cells is largely mediated by tyrosine-phosphorylated PKD2. These data present a novel mechanism of Bcr-Abl-induced nuclear factor kappaB 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.

• Authors: Tamara Mihailovic, Martin Marx, Alexandra Auer, Johan Van Lint, Mathias Schmid, Christoph Weber, Thomas Seufferlein
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 24 Pg. 8939-44 (Dec 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15604256 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoenzymes
• NF-kappa B
• Protein Kinase D2
• Protein Kinases
• Fusion Proteins, bcr-abl

Topics

• Cell Line, Tumor
• Fusion Proteins, bcr-abl (metabolism)
• Humans
• Isoenzymes
• Leukemia, Myeloid (enzymology, genetics, metabolism)
• Mutagenesis, Site-Directed
• NF-kappa B (metabolism)
• Oxidative Stress
• Phosphorylation
• Protein Kinase D2
• Protein Kinases (genetics, metabolism)
• Protein Structure, Tertiary
• Transfection