title: E-cadherin phosphorylation by protein kinase D1/protein kinase C{mu} is associated with altered cellular aggregation and motility in prostate cancer.
abstract: 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 mu (PKCmu)] 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.
authors.affiliation: Urological Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Jaggi
authors.forename: Prema S
authors.initials: PS
authors.lastname: Rao
authors.forename: David J
authors.initials: DJ
authors.lastname: Smith
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Wheelock
authors.forename: Keith R
authors.initials: KR
authors.lastname: Johnson
authors.forename: George P
authors.initials: GP
authors.lastname: Hemstreet
authors.forename: K C
authors.initials: KC
authors.lastname: Balaji
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002449:Cell Aggregation / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015820:Cadherins; D002227:Carbazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; C081021:Go 6976; D049452:Green Fluorescent Proteins; C089212:protein kinase D; D011493:Protein Kinase C