PKC-delta binds to E-cadherin and mediates EGF-induced cell scattering.
EGF is known to affect adherens junctions and disrupt cell-cell adhesion in a variety of carcinomas but the underlying mechanisms are not completely understood. Using human tumor epithelial cells overexpressing EGFR we demonstrated that EGF-induced cell scattering was mediated by protein kinase C-delta (PKC-delta). PKC-delta knockdown by siRNA significantly inhibited EGF-induced internalization of E-cadherin into the cytoplasm and blocked cell scattering. EGF phosphorylated PKC-delta at Y311 and ectopic expression of the mutant Y311F prevented PKC-delta binding to E-cadherin and EGF-induced cell scattering. Moreover, depletion of Src using siRNA decreased EGF-induced phosphorylation of PKC-delta at Y311 and blocked scattering. Finally, EGF reduced expression of the tight junction protein, occludin, and this effect was also mediated by PKC-delta through Src. In summary, PKC-delta mediated the effects of EGF on adherens and tight junctions thereby playing an important role in cell-cell adhesion with possible wider implications in tumor metastasis or epithelial-to-mesenchymal transition.
Singh
Raghvendra
R
Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Amherst, NY 14260-4200, USA.
Lei
Pedro
P
Andreadis
Stelios T
ST
D019943:Amino Acid Substitution; D015820:Cadherins / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002294:Carcinoma, Squamous Cell; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics; D005419:Flavonoids / Q000494:pharmacology; D052816:Foreskin / Q000166:cytology / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D007668:Kidney / Q000196:embryology; D008297:Male; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology
D015820:Cadherins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051745:Protein Kinase C-delta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one