Journal
ONCOTARGET
Volume 7, Issue 24, Pages 37260-37276Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9403
Keywords
PKC delta; E-cadherin; cell junction; phosphorylation
Categories
Funding
- Ministry of Science and Technology, Taiwan [NSC103-2320-B-005-008-MY3, NSC102-2320-B-005-005-MY3]
- National Health Research Institutes, Taiwan [NHRI-EX101-10103BI]
- Aiming Top University plan from the Ministry of Education, Taiwan
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Proper control of cell-cell adhesion is crucial for embryogenesis and tissue homeostasis. In this study, we show that protein kinase C (PKC)delta, a member of the novel PKC subfamily, localizes at cell-cell contacts of epithelial cells through its C2-like domain in an F-actin-dependent manner. Upon hepatocyte growth factor stimulation, PKC delta is phosphorylated and activated by Src, which then phosphorylates E-cadherin at Thr790. Phosphorylation of E-cadherin at Thr790 diminishes its interaction with beta-catenin and impairs the homophilic interaction between the ectodomains of E-cadherin. The suppression of PKCd by its dominant-negative mutants or specific short-hairpin RNA inhibits the disruption of cell-cell adhesions induced by hepatocyte growth factor. Elevated PKCd expression in cancer cells is correlated with increased phosphorylation of E-cadherin at Thr790, reduced binding of E-cadherin to beta-catenin, and poor homophilic interaction between E-cadherin. Analysis of surgical specimens confirmed that PKCd is overexpressed in cervical cancer tissues, accompanied by increased phosphorylation of E-cadherin at Thr790. Together, our findings unveil a negative role for PKCd in cell-cell adhesion through phosphorylation of E-cadherin.
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