| Structural highlights
Function
NEK2_HUMAN Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGOL1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Isoform 1 phosphorylates and activates NEK11 in G1/S-arrested cells. Isoform 2, which is not present in the nucleolus, does not.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Mitosis is controlled by multiple protein kinases, many of which are abnormally expressed in human cancers. Nek2, Nek6, Nek7, and Nek9 are NIMA-related kinases essential for proper mitotic progression. We determined the atomic structure of Nek7 and discovered an autoinhibited conformation that suggests a regulatory mechanism not previously described in kinases. Additionally, Nek2 adopts the same conformation when bound to a drug-like molecule. In both structures, a tyrosine side chain points into the active site, interacts with the activation loop, and blocks the alphaC helix. Tyrosine mutants of Nek7 and the related kinase Nek6 are constitutively active. The activity of Nek6 and Nek7, but not the tyrosine mutant, is increased by interaction with the Nek9 noncatalytic C-terminal domain, suggesting a mechanism in which the tyrosine is released from its autoinhibitory position. The autoinhibitory conformation is common to three Neks and provides a potential target for selective kinase inhibitors.
An autoinhibitory tyrosine motif in the cell-cycle-regulated Nek7 kinase is released through binding of Nek9.,Richards MW, O'Regan L, Mas-Droux C, Blot JM, Cheung J, Hoelder S, Fry AM, Bayliss R Mol Cell. 2009 Nov 25;36(4):560-70. PMID:19941817[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hames RS, Fry AM. Alternative splice variants of the human centrosome kinase Nek2 exhibit distinct patterns of expression in mitosis. Biochem J. 2002 Jan 1;361(Pt 1):77-85. PMID:11742531
- ↑ Lou Y, Yao J, Zereshki A, Dou Z, Ahmed K, Wang H, Hu J, Wang Y, Yao X. NEK2A interacts with MAD1 and possibly functions as a novel integrator of the spindle checkpoint signaling. J Biol Chem. 2004 May 7;279(19):20049-57. Epub 2004 Feb 20. PMID:14978040 doi:10.1074/jbc.M314205200
- ↑ Faragher AJ, Fry AM. Nek2A kinase stimulates centrosome disjunction and is required for formation of bipolar mitotic spindles. Mol Biol Cell. 2003 Jul;14(7):2876-89. Epub 2003 Apr 17. PMID:12857871 doi:10.1091/mbc.E03-02-0108
- ↑ Lou Y, Xie W, Zhang DF, Yao JH, Luo ZF, Wang YZ, Shi YY, Yao XB. Nek2A specifies the centrosomal localization of Erk2. Biochem Biophys Res Commun. 2004 Aug 20;321(2):495-501. PMID:15358203 doi:10.1016/j.bbrc.2004.06.171
- ↑ Yao J, Fu C, Ding X, Guo Z, Zenreski A, Chen Y, Ahmed K, Liao J, Dou Z, Yao X. Nek2A kinase regulates the localization of numatrin to centrosome in mitosis. FEBS Lett. 2004 Sep 24;575(1-3):112-8. PMID:15388344 doi:10.1016/j.febslet.2004.08.047
- ↑ Noguchi K, Fukazawa H, Murakami Y, Uehara Y. Nucleolar Nek11 is a novel target of Nek2A in G1/S-arrested cells. J Biol Chem. 2004 Jul 30;279(31):32716-27. Epub 2004 May 25. PMID:15161910 doi:10.1074/jbc.M404104200
- ↑ Mi J, Guo C, Brautigan DL, Larner JM. Protein phosphatase-1alpha regulates centrosome splitting through Nek2. Cancer Res. 2007 Feb 1;67(3):1082-9. PMID:17283141 doi:10.1158/0008-5472.CAN-06-3071
- ↑ Fu G, Ding X, Yuan K, Aikhionbare F, Yao J, Cai X, Jiang K, Yao X. Phosphorylation of human Sgo1 by NEK2A is essential for chromosome congression in mitosis. Cell Res. 2007 Jul;17(7):608-18. PMID:17621308 doi:10.1038/cr.2007.55
- ↑ Wu W, Baxter JE, Wattam SL, Hayward DG, Fardilha M, Knebel A, Ford EM, da Cruz e Silva EF, Fry AM. Alternative splicing controls nuclear translocation of the cell cycle-regulated Nek2 kinase. J Biol Chem. 2007 Sep 7;282(36):26431-40. Epub 2007 Jul 11. PMID:17626005 doi:10.1074/jbc.M704969200
- ↑ Bahmanyar S, Kaplan DD, Deluca JG, Giddings TH Jr, O'Toole ET, Winey M, Salmon ED, Casey PJ, Nelson WJ, Barth AI. beta-Catenin is a Nek2 substrate involved in centrosome separation. Genes Dev. 2008 Jan 1;22(1):91-105. Epub 2007 Dec 17. PMID:18086858 doi:10.1101/gad.1596308
- ↑ Du J, Cai X, Yao J, Ding X, Wu Q, Pei S, Jiang K, Zhang Y, Wang W, Shi Y, Lai Y, Shen J, Teng M, Huang H, Fei Q, Reddy ES, Zhu J, Jin C, Yao X. The mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability. Oncogene. 2008 Jul 3;27(29):4107-14. doi: 10.1038/onc.2008.34. Epub 2008 Feb 25. PMID:18297113 doi:10.1038/onc.2008.34
- ↑ Liu Q, Hirohashi Y, Du X, Greene MI, Wang Q. Nek2 targets the mitotic checkpoint proteins Mad2 and Cdc20: a mechanism for aneuploidy in cancer. Exp Mol Pathol. 2010 Apr;88(2):225-33. doi: 10.1016/j.yexmp.2009.12.004. Epub, 2009 Dec 23. PMID:20034488 doi:10.1016/j.yexmp.2009.12.004
- ↑ Mardin BR, Lange C, Baxter JE, Hardy T, Scholz SR, Fry AM, Schiebel E. Components of the Hippo pathway cooperate with Nek2 kinase to regulate centrosome disjunction. Nat Cell Biol. 2010 Dec;12(12):1166-76. doi: 10.1038/ncb2120. Epub 2010 Nov 14. PMID:21076410 doi:10.1038/ncb2120
- ↑ Richards MW, O'Regan L, Mas-Droux C, Blot JM, Cheung J, Hoelder S, Fry AM, Bayliss R. An autoinhibitory tyrosine motif in the cell-cycle-regulated Nek7 kinase is released through binding of Nek9. Mol Cell. 2009 Nov 25;36(4):560-70. PMID:19941817 doi:10.1016/j.molcel.2009.09.038
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