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非典型蛋白激酶 C 使 Par6 磷酸化,从而促进转化生长因子 β 诱导的上皮间质转化。

Atypical protein kinase C phosphorylates Par6 and facilitates transforming growth factor β-induced epithelial-to-mesenchymal transition.

机构信息

Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.

出版信息

Mol Cell Biol. 2013 Mar;33(5):874-86. doi: 10.1128/MCB.00837-12. Epub 2012 Dec 17.

Abstract

Epithelial-to-mesenchymal transition (EMT) is controlled by cellular signaling pathways that trigger the loss of cell-cell adhesion and lead to the restructuring of the cell cytoskeleton. Transforming growth factor β (TGF-β) has been shown to regulate cell plasticity through the phosphorylation of Par6 on a conserved serine residue (S345) by the type II TGF-β receptor. We show here that atypical protein kinase C (aPKC) is an essential component to this signaling pathway in non-small-cell lung cancer (NSCLC) cells. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation. In effect, small interfering RNA-targeting aPKC reduces TGF-β-induced RhoA and E-cadherin loss, cell morphology changes, stress fiber production, and the migration of NSCLC cells. Interestingly, reintroduction of a phosphomimetic Par6 (Par6-S345E) into aPKC-silenced cells rescues both RhoA and E-cadherin loss with TGF-β stimulation. In conclusion, our results suggest that aPKCs cooperate with TGF-β receptors to regulate phospho-Par6-dependent EMT and cell migration.

摘要

上皮间质转化 (EMT) 受细胞信号通路控制,这些通路触发细胞间黏附的丧失,并导致细胞细胞骨架的重构。转化生长因子 β (TGF-β) 通过 II 型 TGF-β受体对 Par6 上保守丝氨酸残基 (S345) 的磷酸化来调节细胞可塑性。我们在这里表明,非小细胞肺癌 (NSCLC) 细胞中,非典型蛋白激酶 C (aPKC) 是该信号通路的必需组成部分。我们表明,aPKC、PKCι 通过 Par6 与 TGF-β 受体相互作用,这些蛋白定位于迁移细胞的前缘。此外,TGF-β 受体对 Par6 丝氨酸 345 的磷酸化在存在 aPKC 的情况下增强。aPKC 激酶活性以及与 Par6 的关联对于 Par6 磷酸化很重要。实际上,针对 aPKC 的小干扰 RNA 会减少 TGF-β 诱导的 RhoA 和 E-钙黏蛋白丢失、细胞形态变化、应力纤维生成以及 NSCLC 细胞的迁移。有趣的是,将磷酸化模拟的 Par6 (Par6-S345E) 重新引入到 aPKC 沉默的细胞中,可挽救 TGF-β 刺激引起的 RhoA 和 E-钙黏蛋白丢失。总之,我们的结果表明,aPKC 与 TGF-β 受体合作调节依赖于磷酸化 Par6 的 EMT 和细胞迁移。

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