Lim Nicholas R, Yeap Yvonne Y C, Zhao Teresa T, Yip Yan Y, Wong Shu C, Xu Dan, Ang Ching-Seng, Williamson Nicholas A, Xu Zhiheng, Bogoyevitch Marie A, Ng Dominic C H
J Cell Sci. 2015 Feb 1;128(3):527-40. doi: 10.1242/jcs.157537.
WD40-repeat protein 62 (WDR62) is a spindle pole protein required for normal cell division and neuroprogenitor differentiation during brain development. Microcephaly-associated mutations in WDR62 lead to mitotic mislocalization, highlighting a crucial requirement for precise WDR62 spatiotemporal distribution, although the regulatory mechanisms are unknown. Here, we demonstrate that the WD40-repeat region of WDR62 is required for microtubule association, whereas the disordered C-terminal region regulates cell-cycle-dependent compartmentalization. In agreement with a functional requirement for the WDR62–JNK1 complex during neurogenesis, WDR62 specifically recruits JNK1 (also known as MAPK8), but not JNK2 (also known as MAPK9), to the spindle pole. However, JNK-mediated phosphorylation of WDR62 T1053 negatively regulated microtubule association, and loss of JNK signaling resulted in constitutive WDR62 localization to microtubules irrespective of cell cycle stage. In contrast, we identified that Aurora A kinase (AURKA) and WDR62 were in complex and that AURKA-mediated phosphorylation was required for the spindle localization of WDR62 during mitosis. Our studies highlight complex regulation of WDR62 localization, with opposing roles for JNK and AURKA in determining its spindle association.
WD40重复蛋白62（WDR62）是一种纺锤体极蛋白，在脑发育过程中对正常细胞分裂和神经祖细胞分化是必需的。WDR62中与小头畸形相关的突变导致有丝分裂定位错误，这突出了对精确的WDR62时空分布的关键需求，尽管其调控机制尚不清楚。在这里，我们证明WDR62的WD40重复区域是微管结合所必需的，而无序的C末端区域调节细胞周期依赖性的区室化。与神经发生过程中WDR62-JNK1复合物的功能需求一致，WDR62特异性地将JNK1（也称为MAPK8）而非JNK2（也称为MAPK9）募集到纺锤体极。然而，JNK介导的WDR62 T1053磷酸化负向调节微管结合，并且JNK信号的缺失导致WDR62在不依赖细胞周期阶段的情况下持续定位于微管。相反，我们发现极光激酶A（AURKA）和WDR62形成复合物，并且AURKA介导的磷酸化是有丝分裂期间WDR62纺锤体定位所必需的。我们的研究突出了WDR62定位的复杂调控，其中JNK和AURKA在确定其纺锤体结合方面具有相反的作用。
