Par3 controls epithelial spindle orientation by aPKC-mediated phosphorylation of apical Pins.
Par3 controls epithelial spindle orientation by aPKC-mediated phosphorylation of apical Pins.
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DOI：
10.1016/j.cub.2010.09.032
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发表时间：
2010-10-26
期刊：
影响因子：
9.2
通讯作者：
Macara, Ian G.
中科院分区：
文献类型：
--
作者：
Hao, Yi;Du, Quansheng;Chen, Xinyu;Zheng, Zhen;Balsbaugh, Jeremy L.;Maitra, Sushmit;Shabanowitz, Jeffrey;Hunt, Donald F.;Macara, Ian G.
上皮层的形成要求细胞分裂发生在层的平面上。在有丝分裂过程中，纺锤体两极对齐，因此星形微管接触侧皮质。将哺乳动物的Pins蛋白限制在外侧皮质对这一过程至关重要。通过Cdc 42和非典型蛋白激酶C（aPKC）的信号传导缺陷也会导致纺锤体方向错误。当上皮囊肿在3D培养中生长时，错误的方向会产生多个管腔。我们现在表明，沉默的极性蛋白Par 3的原因纺锤体错误取向MDCK细胞胞囊。Par 3的沉默也破坏了aPKC与顶端皮质的联系，但顶端栓系的aPKC的表达挽救了正常的管腔形成。在有丝分裂过程中，Pins在不存在Par 3的情况下或通过抑制aPKC而错误定位于顶端表面。活性aPKC增加Ser 401上的Pins磷酸化，其募集14-3-3蛋白。14-3-3结合抑制Pin与Gαi的结合，Pin通过G αi附着于皮质。Pins S401 A突变体错误定位在细胞皮质上，并导致纺锤体取向和管腔缺陷。Par 3/aPKC极性蛋白通过从顶端皮质排除针来确保上皮细胞分裂期间正确的纺锤体极取向。顶端aPKC磷酸化Pins，导致14-3-3的募集和与Gαi结合的抑制，因此Pins福尔斯从皮质脱落。在缺乏功能性排斥机制的情况下，星形微管可以与整个上皮皮质上的Pins结合，导致随机的纺锤体极点取向。
Formation of epithelial sheets requires that cell division occurs in the plane of the sheet. During mitosis, spindle poles align so the astral microtubules contact the lateral cortex. Confinement of the mammalian Pins protein to the lateral cortex is essential for this process. Defects in signaling through Cdc42 and atypical protein kinase C (aPKC) also cause spindle misorientation. When epithelial cysts are grown in 3D cultures, mis-orientation creates multiple lumens. We now show that silencing of the polarity protein Par3 causes spindle mis-orientation in MDCK cell cysts. Silencing of Par3 also disrupts aPKC association with the apical cortex, but expression of an apically-tethered aPKC rescues normal lumen formation. During mitosis, Pins is mislocalized to the apical surface in the absence of Par3, or by inhibition of aPKC. Active aPKC increases Pins phosphorylation on Ser401, which recruits 14-3-3 protein. 14-3-3 binding inhibits association of Pins with Gαi, through which Pins attaches to the cortex. A Pins S401A mutant mislocalizes over the cell cortex and causes spindle orientation and lumen defects. The Par3/aPKC polarity proteins ensure correct spindle pole orientation during epithelial cell division by excluding Pins from the apical cortex. Apical aPKC phosphorylates Pins, which results in the recruitment of 14-3-3 and inhibition of binding to Gαi, so the Pins falls off the cortex. In the absence of a functional exclusion mechanism, astral microtubules can associate with Pins over the entire epithelial cortex, resulting in randomized spindle pole orientation.
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影响因子：
10.5
作者：
McCaffrey, Luke Martin;Macara, Ian G.
通讯作者：
Macara, Ian G.
DOI：
10.1152/ajprenal.00131.2001
发表时间：
2002-06-01
影响因子：
4.2
作者：
Li, Y;Li, J;Kershaw, DB
通讯作者：
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影响因子：
11.4
作者：
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通讯作者：
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影响因子：
64.5
作者：
Morais-de-Sá E;Mirouse V;St Johnston D
通讯作者：
St Johnston D
影响因子：
64.5
作者：
Johnston CA;Hirono K;Prehoda KE;Doe CQ
通讯作者：
Doe CQ