Kinase Subfamily NEK8
Kinase Classification: Group Other: Family NEK: Subfamily NEK8
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Evolution
NEK8 is found in most holozoans (animals + choanoflagellates). It has a single copy in mammals (NEK8) and Drosophila (CG10951) but has duplicated in C. elegans (nekl-1/ZC581.1, nekl-2/Y39G10AR.4), sea urchin, sponge and elsewhere.
Domain Structure
Like NEK9, members have an N-terminal kinase domain followed by a set of 7 RCC1 (regulator of chromosome condensation) domains. Many invertebrates have an additional N-terminal domain that is lost in bony vertebrates.
Functions
NEK8 has chromosomal and cilium functions, like many other NEKs. Human NEK8 mutations are associated with cardiac, renal and liver defects [1, 2]. NEK8 is associated with centrosomes in dividing cells and with the proximal cilium in non-diving cells [3], both of which require kinase activity and the RCC1 domain. Once cilia are formed, NEK8 is degraded by the proteasome, probably through binding of pVHL [4]
NEK8 is phosphorylated on the activation loop, T162, and mutations to this site increase or decrease activity, as expected [3]
References
- Hassan S, Wolf MTF, Umaña LA, Malik S, Uddin N, Andersen J, and Aqul A. Homozygous NEK8 Mutations in Siblings With Neonatal Cholestasis Progressing to End-stage Liver, Renal, and Cardiac Disease. J Pediatr Gastroenterol Nutr. 2020 Jan;70(1):e19-e22. DOI:10.1097/MPG.0000000000002517 |
- Rajagopalan R, Grochowski CM, Gilbert MA, Falsey AM, Coleman K, Romero R, Loomes KM, Piccoli DA, Devoto M, and Spinner NB. Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies. Am J Med Genet A. 2016 Mar;170(3):750-3. DOI:10.1002/ajmg.a.37512 |
- Zalli D, Bayliss R, and Fry AM. The Nek8 protein kinase, mutated in the human cystic kidney disease nephronophthisis, is both activated and degraded during ciliogenesis. Hum Mol Genet. 2012 Mar 1;21(5):1155-71. DOI:10.1093/hmg/ddr544 |
- Ding XF, Chen J, Zhou J, Chen G, and Wu YL. Never-in-mitosis A-related kinase 8, a novel target of von-Hippel-Lindau tumor suppressor protein, promotes gastric cancer cell proliferation. Oncol Lett. 2018 Nov;16(5):5900-5906. DOI:10.3892/ol.2018.9328 |
