Iimori Makoto, Watanabe Sugiko, Kiyonari Shinichi, Matsuoka Kazuaki, Sakasai Ryo, Saeki Hiroshi, Oki Eiji, Kitao Hiroyuki, Maehara Yoshihiko
Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Nat Commun. 2016 Mar 31;7:11117. doi: 10.1038/ncomms11117.
Temporal regulation of microtubule dynamics is essential for proper progression of mitosis and control of microtubule plus-end tracking proteins by phosphorylation is an essential component of this regulation. Here we show that Aurora B and CDK1 phosphorylate microtubule end-binding protein 2 (EB2) at multiple sites within the amino terminus and a cluster of serine/threonine residues in the linker connecting the calponin homology and end-binding homology domains. EB2 phosphorylation, which is strictly associated with mitotic entry and progression, reduces the binding affinity of EB2 for microtubules. Expression of non-phosphorylatable EB2 induces stable kinetochore microtubule dynamics and delays formation of bipolar metaphase plates in a microtubule binding-dependent manner, and leads to aneuploidy even in unperturbed mitosis. We propose that Aurora B and CDK1 temporally regulate the binding affinity of EB2 for microtubules, thereby ensuring kinetochore microtubule dynamics, proper mitotic progression and genome stability.
微管动力学的时间调控对于有丝分裂的正常进行至关重要，通过磷酸化作用对微管正端追踪蛋白的调控是这一调控的重要组成部分。在此我们表明，极光激酶B（Aurora B）和细胞周期蛋白依赖性激酶1（CDK1）在氨基末端的多个位点以及连接钙调蛋白同源结构域和末端结合同源结构域的接头中的一簇丝氨酸/苏氨酸残基处磷酸化微管末端结合蛋白2（EB2）。EB2磷酸化与有丝分裂的进入和进程密切相关，它降低了EB2与微管的结合亲和力。不可磷酸化的EB2的表达以微管结合依赖的方式诱导稳定的动粒微管动力学，并延迟双极中期板的形成，甚至在未受干扰的有丝分裂中也会导致非整倍体。我们提出，极光激酶B和CDK1在时间上调控EB2与微管的结合亲和力，从而确保动粒微管动力学、正常的有丝分裂进程和基因组稳定性。
