aPKCζ cortical loading is associated with Lgl cytoplasmic release and tumor growth in Drosophila and human epithelia
aPKCζ cortical loading is associated with Lgl cytoplasmic release and tumor growth in Drosophila and human epithelia
复制标题
DOI：
10.1038/sj.onc.1210389
复制
发表时间：
2007-08-30
期刊：
影响因子：
8
通讯作者：
Pession, A.
中科院分区：
文献类型：
--
作者：
Grifoni, D.;Garoia, F.;Pession, A.
非典型蛋白激酶C （aPKC）和致命巨幼虫（Lgl）调节果蝇和哺乳动物上皮的顶基极性。在顶域，aPKC磷酸化并取代Lgl，这反过来又保持aPKC在基底外侧区域的无活性。这两种蛋白的相互排斥似乎对正确的上皮结构和功能至关重要。本研究表明，皮质aPKC加载诱导果蝇想象上皮中Lgl的细胞质释放和大量过度生长，而细胞质表达不会改变增殖和上皮的整体结构。由于人类存在两种aPKC亚型（iota和zeta），并且我们之前发现果蝇Lgl是人类巨幼虫-1 （Hugl-1）蛋白的功能同源物，因此我们探讨了人类上皮疾病中是否存在相同的相互排斥机制，并研究了aPKC iota、aPKC zeta和Hugl-1在卵巢表面上皮衍生的癌症中的定位。在黏液和浆液组织型中，aPKC zeta表现为顶端到皮层的再分布，Hugl-1表现为膜到细胞质的释放，完美地概括了果蝇模型。尽管最近的一些研究支持aPKCi在人类癌症中的过度表达，但我们的研究结果表明aPKC zeta在根尖-基底极性松动中起关键作用，这一机制似乎是由蛋白质定位的变化而不是蛋白质丰度的变化驱动的。
Atypical protein kinase C ( aPKC) and Lethal giant larvae ( Lgl) regulate apical-basal polarity in Drosophila and mammalian epithelia. At the apical domain, aPKC phosphorylates and displaces Lgl that, in turn, maintains aPKC inactive at the basolateral region. The mutual exclusion of these two proteins seems to be crucial for the correct epithelial structure and function. Here we show that a cortical aPKC loading induces Lgl cytoplasmic release and massive overgrowth in Drosophila imaginal epithelia, whereas a cytoplasmic expression does not alter proliferation and epithelial overall structure. As two aPKC isoforms ( iota and zeta) exist in humans and we previously showed that Drosophila Lgl is the functional homologue of the Human giant larvae-1 ( Hugl-1) protein, we argued if the same mechanism of mutual exclusion could be impaired in human epithelial disorders and investigated aPKC iota, aPKC zeta and Hugl-1 localization in cancers deriving from ovarian surface epithelium. Both in mucinous and serous histotypes, aPKC zeta showed an apical-to-cortical redistribution and Hugl-1 showed a membrane-to-cytoplasm release, perfectly recapitulating the Drosophila model. Although several recent works support a causative role for aPKCi overexpression in human carcinomas, our results suggest a key role for aPKC zeta in apical-basal polarity loosening, a mechanism that seems to be driven by changes in protein localization rather than in protein abundance.