Abstract 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 δ and η 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.

中文翻译：

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蛋白激酶C调控卵巢癌细胞膜分子间的复合物

摘要 整合性和外周细胞粘附分子 (CAM) 的整合复杂阵列之间的相互作用受到激酶（例如蛋白激酶 C (PKC)）的严格控制，以响应外部或内部力和/或信号传导的变化。专注于 EpCAM-密蛋白-四跨膜蛋白驱动的卵巢癌复合物，我们描述了一系列事件，通过这些事件，位于四跨膜蛋白富集的微结构域中的 PKC 的作用影响了相互作用，并在 PKC 激活剂和抑制剂处理的卵巢癌细胞中进行了免疫沉淀和异种移植卵巢癌小鼠模型。激活的 PKC 亚型与四跨膜蛋白相关，并诱导密蛋白磷酸化状态的可检测变化。这些结果表明 PKC 靶向 claudin-4 ad -7。磷酸化，特别是通过 PKC δ 和 η 对 claudin-4、-7 和 EpCAM 之间的相互作用很重要。这些结果代表了直接证据，即 PKC 对密蛋白的磷酸化在 EpCAM-密蛋白-四跨膜蛋白复合物形成中起作用，以允许这些复合物在体外和体内在卵巢癌进展和转移中起作用。