Kinase Subfamily NEK11
Kinase Classification: Group Other: Family NEK: Subfamily NEK11
Evolution
NEK11 is found as a single copy gene in most animals, but is lost in Drosophila and C. elegans.
Domain Structure
All NEK11 have a kinase domain near the N-terminus and a long C-terminal extension without known domains, though the very C-terminal region is well conserved and predicted to be helical. Human NEK1 has 3 splice variants with truncated C-terminal domains [1].
Functions
NEK11 is involved in the G2/M mitotic checkpoint. CHK1 phosphorylates NEK11 on S273, activating it to phosphorylate the mitotic phosphatase, CDC25A on the phosphodegron sites S79, S82 and S88, leading to its degradation via bTrCP binding and ubiquitination, and blocking cell cycle progression [2]. NEK11 is induced by DNA damage and appears to be involved in the S phase checkpoint [3].
NEK11 is a substrate of NEK2, and the two proteins have been co-immunoprecipitated [4], which depends on the NEK11 C-terminal region (residues 385-467) and NEK2 being catalytically active. Several experiments suggested that the C-terminal region of NEK11 binds and autoinhibits the kinase domain, and that NEK2 phosphorylation on multiple sites relieves this inhibition.
NEK11 was also shown to regulated asymmetric cell division during mouse oocyte meiotic maturation [5].
NEK11 expression is increased by ionizing radiation, which induces the DNA damage response [6]. Knockdown of NEK11 in cancer cells increased p53-dependent apoptosis and blocked the G2/M arrest normally induced by ionizing radiation or chemotherapy [1].
References
- Sabir SR, Sahota NK, Jones GD, and Fry AM. Loss of Nek11 Prevents G2/M Arrest and Promotes Cell Death in HCT116 Colorectal Cancer Cells Exposed to Therapeutic DNA Damaging Agents. PLoS One. 2015;10(10):e0140975. DOI:10.1371/journal.pone.0140975 |
- Sørensen CS, Melixetian M, Klein DK, and Helin K. NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling. Cell Cycle. 2010 Feb 1;9(3):450-5. DOI:10.4161/cc.9.3.10513 |
- Guo L, Wang ZB, Wang HH, Zhang T, Qi ST, Ouyang YC, Hou Y, and Sun QY. Nek11 regulates asymmetric cell division during mouse oocyte meiotic maturation. Biochem Biophys Res Commun. 2016 Jun 10;474(4):667-672. DOI:10.1016/j.bbrc.2016.05.002 |
- Noguchi K, Fukazawa H, Murakami Y, and Uehara Y. Nek11, a new member of the NIMA family of kinases, involved in DNA replication and genotoxic stress responses. J Biol Chem. 2002 Oct 18;277(42):39655-65. DOI:10.1074/jbc.M204599200 |
- Noguchi K, Fukazawa H, Murakami Y, and 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. DOI:10.1074/jbc.M404104200 |
