Kinase Subfamily NEK4

Kinase Classification: Group Other: Family NEK: Subfamily NEK4

Evolution

NEK4 is found as a single copy gene in animals and Dictyostelium. It is thought to be secondarily lost from insects and nematodes as well as fungi. Plants have an expansion of NEKs that look broadly like NEK4 but are not clear orthologs.

Domain Structure

NEK4 has an N-terminal kinase domain and a typically longer C-terminal extension with no known domains.

Functions

Mammalian NEK4 has a wide variety of functions including several shared with other NEK subfamilies. Shared functions include cilium integrity [1], autophagy, and mitochondrial functions [2, 3], while likely unique functions include cell cycle arrest in response to dsDNA damage [4] and entry into replicative senescence [4], along with epithelial-to-mesenchymal transition [5].

NEK4 variants have been genetically linked to Schizophrenia and Bipolar disorder [6, 7, 8].

Interactome analysis implicates NEK4 in DNA damage response, cilia maintenance and microtubule maintenance as well as several other functions, including splicing, apoptosis and stress response [9].

References

1. Coene KL, Mans DA, Boldt K, Gloeckner CJ, van Reeuwijk J, Bolat E, Roosing S, Letteboer SJ, Peters TA, Cremers FP, Ueffing M, and Roepman R. The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase. Hum Mol Genet. 2011 Sep 15;20(18):3592-605. DOI:10.1093/hmg/ddr280 |
2. Basei FL, E Silva IR, Dias PRF, Ferezin CC, Peres de Oliveira A, Issayama LK, Moura LAR, da Silva FR, and Kobarg J. The Mitochondrial Connection: The Nek Kinases' New Functional Axis in Mitochondrial Homeostasis. Cells. 2024 Mar 7;13(6). DOI:10.3390/cells13060473 |
3. Basei FL, de Castro Ferezin C, Rodrigues de Oliveira AL, Muñoz JP, Zorzano A, and Kobarg J. Nek4 regulates mitochondrial respiration and morphology. FEBS J. 2022 Jun;289(11):3262-3279. DOI:10.1111/febs.16343 |
4. Nguyen CL, Possemato R, Bauerlein EL, Xie A, Scully R, and Hahn WC. Nek4 regulates entry into replicative senescence and the response to DNA damage in human fibroblasts. Mol Cell Biol. 2012 Oct;32(19):3963-77. DOI:10.1128/MCB.00436-12 |
5. Ding NH, Zhang L, Xiao Z, Rong ZX, Li Z, He J, Chen L, Ou DM, Liao WH, and Sun LQ. NEK4 kinase regulates EMT to promote lung cancer metastasis. J Cell Mol Med. 2018 Dec;22(12):5877-5887. DOI:10.1111/jcmm.13857 |
6. Zhang C, Yang Z, Li X, Zhao L, Guo W, Deng W, Wang Q, Hu X, Li M, Sham PC, Xiao X, and Li T. Unraveling NEK4 as a Potential Drug Target in Schizophrenia and Bipolar I Disorder: A Proteomic and Genomic Approach. Schizophr Bull. 2024 Aug 27;50(5):1185-1196. DOI:10.1093/schbul/sbae094 |
7. Li X, Shen A, Zhao Y, and Xia J. Mendelian Randomization Using the Druggable Genome Reveals Genetically Supported Drug Targets for Psychiatric Disorders. Schizophr Bull. 2023 Sep 7;49(5):1305-1315. DOI:10.1093/schbul/sbad100 |
8. Shang MY, Zhang CY, Wu Y, Wang L, Wang C, and Li M. Genetic associations between bipolar disorder and brain structural phenotypes. Cereb Cortex. 2023 May 24;33(11):6990-7000. DOI:10.1093/cercor/bhad014 |
9. Basei FL, Meirelles GV, Righetto GL, Dos Santos Migueleti DL, Smetana JH, and Kobarg J. New interaction partners for Nek4.1 and Nek4.2 isoforms: from the DNA damage response to RNA splicing. Proteome Sci. 2015;13:11. DOI:10.1186/s12953-015-0065-6 |