The interactions between the integrated complex array of integral and peripheral cell adhesion molecules (CAMs) are tightly controlled by kinases such as Protein Kinase C (PKC) in response to changes in external or internal forces and/or signaling. Focusing on the complex of EpCAM-claudin-tetraspanin-driven ovarian cancer, we described a sequence of events by which role of PKCs located in the tetraspanin enriched microdomains affected on the interactions and performed immunoprecipitations in PKC activator and inhibitors-treated ovarian cancer cells and xenograft ovarian cancer mouse models. Activated PKC isoforms associated with tetraspanins and induced detectable changes in the claudin phosphorylation state. These results suggest that PKC targets claudin-4 ad -7. Phosphorylation, especially by PKC delta and eta of claudins was important for the interactions between claudin-4, -7 and EpCAM. These results represent the direct evidence that phosphorylation of claudins by PKCs functions in the EpCAM-claudin-tetraspanin complex formation to allow these complexes to operate in ovarian cancer progression and metastasis in vitro and in vivo.