KIBRA Suppresses Apical Exocytosis through Inhibition of aPKC Kinase Activity in Epithelial Cells
KIBRA Suppresses Apical Exocytosis through Inhibition of aPKC Kinase Activity in Epithelial Cells
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DOI：
10.1016/j.cub.2011.03.029
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发表时间：
2011-04
期刊：
影响因子：
9.2
通讯作者：
Yohei Yoshihama;K. Sasaki;Yosuke Horikoshi;A. Suzuki;T. Ohtsuka;F. Hakuno;Shin-ichiro Takahashi;
中科院分区：
文献类型：
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作者：
Yohei Yoshihama;K. Sasaki;Yosuke Horikoshi;A. Suzuki;T. Ohtsuka;F. Hakuno;Shin-ichiro Takahashi;
上皮细胞具有顶侧-基底侧极性，并在顶侧边界形成紧密连接（TJ），将顶侧和基底侧膜区域分开。PAR 3-aPKC-PAR 6复合物在组织形态发生过程中的TJ形成和顶端结构域发育中起核心作用[1-4]。aPKC激酶活性的失活和过度活化破坏膜极性[5-8]。抑制活性aPKC的机制尚不清楚。KIBRA是Hippo通路的上游调节因子，可调节果蝇的组织大小[9-11]，并可与aPKC结合[12，13]。然而，KIBRA和PAR 3-aPKC-PAR 6复合物之间的关系仍然未知。我们报告说，KIBRA结合PAR 3-aPKC-PAR 6复合物，并定位于上皮组织和细胞中的TJ和顶端结构域。KIBRA的敲除导致MDCK三维囊肿中顶端结构域的扩展，并通过增强的从头顶端胞吐抑制含顶端空泡的形成。这些表型通过抑制aPKC而恢复。此外，KIBRA在体外直接抑制aPKC的激酶活性。这些结果强烈支持KIBRA通过直接抑制PAR 3-aPKC-PAR 6复合物中的aPKC激酶活性来抑制顶端胞吐作用，从而调节上皮细胞极性的观点。
Epithelial cells possess apical-basolateral polarity and form tight junctions (TJs) at the apical-lateral border, separating apical and basolateral membrane domains. The PAR3-aPKC-PAR6 complex plays a central role in TJ formation and apical domain development during tissue morphogenesis [1–4]. Inactivation and overactivation of aPKC kinase activity disrupts membrane polarity [5–8]. The mechanism that suppresses active aPKC is unknown. KIBRA, an upstream regulator of the Hippo pathway, regulates tissue size inDrosophila[9–11] and can bind to aPKC [12, 13]. However, the relationship between KIBRA and the PAR3-aPKC-PAR6 complex remains unknown. We report that KIBRA binds to the PAR3-aPKC-PAR6 complex and localizes at TJs and apical domains in epithelial tissues and cells. The knockdown of KIBRA causes expansion of the apical domain in MDCK three-dimensional cysts and suppresses the formation of apical-containing vacuoles through enhanced de novo apical exocytosis. These phenotypes are restored by inhibition of aPKC. In addition, KIBRA directly inhibits the kinase activity of aPKC in vitro. These results strongly support the notion that KIBRA regulates epithelial cell polarity by suppressing apical exocytosis through direct inhibition of aPKC kinase activity in the PAR3-aPKC-PAR6 complex.