Activation of Discs large by aPKC aligns the mitotic spindle to the polarity axis during asymmetric cell division
Activation of Discs large by aPKC aligns the mitotic spindle to the polarity axis during asymmetric cell division
复制标题
DOI：
10.7554/elife.32137
复制
发表时间：
2017-11-29
期刊：
影响因子：
7.7
通讯作者：
Prehoda, Kenneth E.
中科院分区：
文献类型：
--
作者：
Golub, Ognjen;Wee, Brett;Prehoda, Kenneth E.
不对称分裂通过产生具有不同命运的子细胞来产生细胞多样性。在动物中，有丝分裂纺锤体与Par复合体极化命运决定因子对齐，确保命运决定因子皮质结构域被劈裂沟一分为二。在此，我们研究了果蝇神经母细胞不对称分裂过程中纺锤体取向与极性耦合的机制。我们发现肿瘤抑制因子disc large （Dig）将Par复合物组分非典型蛋白激酶C （aPKC）与基本纺锤体取向因子GukHolder （GukH）连接起来。Dig被其SH3和GK结构域之间的分子内相互作用自动抑制，阻止Dig在缺乏aPKC的皮质位点与GukH相互作用。当与aPKC共定位时，Dig在其SH3结构域磷酸化，从而破坏自身抑制并允许GukH通过GK结构域募集。我们的工作在不对称细胞分裂过程中建立了极性和纺锤体取向机制之间的分子联系。
Asymmetric division generates cellular diversity by producing daughter cells with different fates. In animals, the mitotic spindle aligns with Par complex polarized fate determinants, ensuring that fate determinant cortical domains are bisected by the cleavage furrow. Here, we investigate the mechanisms that couple spindle orientation to polarity during asymmetric cell division of Drosophila neuroblasts. We find that the tumor suppressor Discs large (Dig) links the Par complex component atypical Protein Kinase C (aPKC) to the essential spindle orientation factor GukHolder (GukH). Dig is autoinhibited by an intramolecular interaction between its SH3 and GK domains, preventing Dig interaction with GukH at cortical sites lacking aPKC. When co-localized with aPKC, Dig is phosphorylated in its SH3 domain which disrupts autoinhibition and allows GukH recruitment by the GK domain. Our work establishes a molecular connection between the polarity and spindle orientation machineries during asymmetric cell division.