A mitotic cascade of NIMA family kinases - Nercc1/Nek9 activates the Nek6 and Nek7 kinases
A mitotic cascade of NIMA family kinases - Nercc1/Nek9 activates the Nek6 and Nek7 kinases
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DOI：
10.1074/jbc.m303663200
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发表时间：
2003-09-12
影响因子：
4.8
通讯作者：
Avruch, J
中科院分区：
文献类型：
--
作者：
Belham, C;Roig, J;Avruch, J
人类中的Nek蛋白激酶家族由11个成员组成，这些成员共享与NIMA相关的氨基末端催化结构域，NIMA是一种参与控制有丝分裂的几个方面的曲霉属激酶，以及不同长度的不同羧基末端尾。Nek 6（314 AA）和Nek 7（303 AA），76%相同，几乎没有非催化序列，但结合到Nerc 1/Nek 9的羧基末端非催化尾部，Nerc 1/Nek 9是一种在有丝分裂中激活的NIMA家族蛋白激酶。显微注射抗Nerc 1抗体导致纺锤体异常和早中期阻滞或染色体错误分离。在此，我们表明，Nek 6的丰度和活性增加有丝分裂过程中，激活需要的Nek 6激活环上的丝氨酸（206）的磷酸化。这种磷酸化和重组Nek 6的活性通过与Nerc 1的活化突变体共表达来刺激。此外，Nercc 1在体外催化原核重组Nek 6在Ser（206）处的直接磷酸化，伴随着Nek 6活性的20-25倍活化; Nercc 1以类似的方式在体外活化Nek 7。Nerc 1/Nek 9可能在有丝分裂期间负责激活Nek 6，并且可能也参与调节Nek 7。这些发现支持了以下结论，即Nercc 1/Nek 9和Nek 6代表了一种新的有丝分裂NIMA家族蛋白激酶级联，其组合功能对有丝分裂进程很重要。
The Nek family of protein kinases in humans is composed of 11 members that share an amino-terminal catalytic domain related to NIMA, an Aspergillus kinase involved in the control of several aspects of mitosis, and divergent carboxyl-terminal tails of varying length. Nek6 (314AA) and Nek7 (303AA), 76% identical, have little noncatalytic sequence but bind to the carboxyl-terminal noncatalytic tail of Nercc1/Nek9, a NIMA family protein kinase that is activated in mitosis. Microinjection of anti-Nercc1 antibodies leads to spindle abnormalities and prometaphase arrest or chromosome missegregation. Herein we show that Nek6 is increased in abundance and activity during mitosis; activation requires the phosphorylation of Ser(206) on the Nek6 activation loop. This phosphorylation and the activity of recombinant Nek6 is stimulated by coexpression with an activated mutant of Nercc1. Moreover, Nercc1 catalyzes the direct phosphorylation of prokaryotic recombinant Nek6 at Ser(206) in vitro concomitant with 20-25-fold activation of Nek6 activity; Nercc1 activates Nek7 in vitro in a similar manner. Nercc1/Nek9 is likely to be responsible for the activation of Nek6 during mitosis and probably participates in the regulation of Nek7 as well. These findings support the conclusion that Nercc1/Nek9 and Nek6 represent a novel cascade of mitotic NIMA family protein kinases whose combined function is important for mitotic progression.