Open AccessThe mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability
Author(s) -
Jinyan Du,
Xin Cai,
Jianhui Yao,
Xia Ding,
Qiulian Wu,
Shiqi Pei,
Kai Jiang,
Yongliang Zhang,
W Wang,
Yunyu Shi,
Ya-Shiuan Lai,
Jilong Shen,
Maikun Teng,
Haojie Huang,
Q Fei,
E. S. P. Reddy,
Jingjing Zhu,
Changjie Jin,
Xuebiao Yao
Publication year - 2008
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/onc.2008.34
Subject(s) - kinetochore , biology , microbiology and biotechnology , mitosis , chromosome segregation , microtubule , spindle apparatus , chromosome instability , aurora b kinase , plk1 , cell division , chromosome , genetics , cell , cell cycle , gene
Loss or gain of whole chromosome, the form of chromosome instability commonly associated with cancers is thought to arise from aberrant chromosome segregation during cell division. Chromosome segregation in mitosis is orchestrated by the interaction of kinetochores with spindle microtubules. Our studies show that NEK2A is a kinetochore-associated protein kinase essential for faithful chromosome segregation. However, it was unclear how NEK2A ensures accurate chromosome segregation in mitosis. Here we show that NEK2A-mediated Hec1 (highly expressed in cancer) phosphorylation is essential for faithful kinetochore microtubule attachments in mitosis. Using phospho-specific antibody, our studies show that NEK2A phosphorylates Hec1 at Ser165 during mitosis. Although such phosphorylation is not required for assembly of Hec1 to the kinetochore, expression of non-phosphorylatable mutant Hec1(S165) perturbed chromosome congression and resulted in a dramatic increase in microtubule attachment errors, including syntelic and monotelic attachments. Our in vitro reconstitution experiment demonstrated that Hec1 binds to microtubule in low affinity and phosphorylation by NEK2A, which prevents aberrant kinetochore-microtubule connections in vivo, increases the affinity of the Ndc80 complex for microtubules in vitro. Thus, our studies illustrate a novel regulatory mechanism in which NEK2A kinase operates a faithful chromosome attachment to spindle microtubule, which prevents chromosome instability during cell division.