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E-Cadherin Phosphorylation by Protein Kinase D1/Protein Kinase Cµ is Associated with Altered Cellular Aggregation and Motility in Prostate Cancer

University of Nebraska Medical Center, Omaha, Nebraska

Requests for reprints: K.C. Balaji, Urological Oncology Research, Urological Surgery, 982360, University of Nebraska Medical Center, Omaha, NE 68198-2360. Phone: 402-559-9041; Fax: 402-559-6529; E-mail: kcbalaji{at}unmc.edu.

The cadherin family of transmembrane glycoproteins plays a critical role in cell-to-cell adhesion and cadherin dysregulation is strongly associated with cancer metastasis and progression. In this study, we report a novel interaction between protein kinase D1 [PKD1; formerly known as protein kinase C µ (PKCµ)] and E-cadherin. PKD1 is a serine/threonine-specific kinase known to play a role in multiple cellular processes including apoptosis, cytoskeleton remodeling, and invasion. Our study shows that PKD1 colocalizes with E-cadherin at cell junctions in LNCaP prostate cancer cells and coimmunoprecipitates with E-cadherin from lysates of LNCaP cells. In vitro kinase assays have shown that PKD1 phosphorylates E-cadherin. Inhibition of PKD1 activity by the selective inhibitor Gö6976 in LNCaP cells resulted in decreased cellular aggregation and overexpression of PKD1 in C4-2 prostate cancer cells increased cellular aggregation and decreased cellular motility. We also validated the PKD1 and E-cadherin colocalization in human prostate cancer tissue by confocal laser scanning microscopy. Our study has identified E-cadherin as a novel substrate of PKD1, and phosphorylation of E-cadherin by PKD1 is associated with increased cellular aggregation and decreased cellular motility in prostate cancer. Because both E-cadherin and PKD1 are known to be dysregulated in prostate cancer, our study identified an important protein-protein interaction influencing the signal transduction system associated with cell adhesion in prostate cancer.

Key Words: E-cadherin • PKD1 • PKCµ • prostate cancer • phosphorylation

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