Protein kinase D signaling in cancer

Protein Kinase D is a serine/threonine kinase that shows responsiveness to phorbol esters and diacylglycerol and is a direct target for Src family kinases, RhoGTPases and protein kinase C. Thus PKD on first view represents a bona fide oncogene and is currently investigated for its potential as a drug target for multiple cancers. This is supported by the discovery that PKD promotes tumor cell survival in response to damaging stresses such as increases in reactive oxygen species, but also enhances cell proliferation and DNA synthesis in response to activation by growth factor and G-protein-coupled receptors. Based on these findings, the development of PKD inhibitors is progressed within the field. However, accumulating reports also suggest that PKD activation suppresses directed cell migration and invasion, suggesting that PKD expression may be needed for early tumorigenic events, but is downregulated during metastatic progression. This chapter describes the known roles of PKD isoenzymes in all aspects of tumor biology as well as the signaling mechanisms they use, and discusses their potential value as drug targets in cancer.