Kinase Subfamily NEK1
Kinase Classification: Group Other: Family NEK: Subfamily NEK1
Evolution
NEK1 is widespread in eukaryotes, though lost in fungi, Drosophila, and C. elegans, correlated with their loss of primary cilium genes. Most species have a single NEK1. Vertebrates have 3 members, NEK1, NEK3, and NEK5, with additional duplications in fish.
Domain Structure
All have an N-terminal kinase domain with varied C-terminal extensions that typically are poorly conserved, though annotated to have coiled-coil and PEST regions and having some sequence conservation between the three proteins. The three vertebrate members have distinctly different lengths, from 500-1200 AA. Invertebrate members are closest to the long form, NEK1, with several conserved regions, indicating that NEK3 and NEK5 are truncated forms.
Functions
NEK3 is the least studied member of the subfamily, and has no known association with cell cycle or DNA damage [1]. It functions downstream of prolactin signaling in breast tissue, which induces phosphorylation on T165 via the Erk pathway. This activation causes cytoskeletal changes that promote migration and invasion [2], including a direct interaction and phosphorylation of paxillin, and upregulation of Rac1 [3]. Prolactin induces an interaction between NEK3 and the VAV2/VAV3 guanine nucleotide exchange factors, and between them and the prolactin receptor [4]. NEK3 was also reported to phosphorylate SNAP29, a t-SNARE protein, on S105, and cause its membrane association [5]
References
- Tanaka K and Nigg EA. Cloning and characterization of the murine Nek3 protein kinase, a novel member of the NIMA family of putative cell cycle regulators. J Biol Chem. 1999 May 7;274(19):13491-7. DOI:10.1074/jbc.274.19.13491 |
- Harrington KM and Clevenger CV. Identification of NEK3 Kinase Threonine 165 as a Novel Regulatory Phosphorylation Site That Modulates Focal Adhesion Remodeling Necessary for Breast Cancer Cell Migration. J Biol Chem. 2016 Oct 7;291(41):21388-21406. DOI:10.1074/jbc.M116.726190 |
- Miller SL, Antico G, Raghunath PN, Tomaszewski JE, and Clevenger CV. Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells. Oncogene. 2007 Jul 12;26(32):4668-78. DOI:10.1038/sj.onc.1210264 |
- Miller SL, DeMaria JE, Freier DO, Riegel AM, and Clevenger CV. Novel association of Vav2 and Nek3 modulates signaling through the human prolactin receptor. Mol Endocrinol. 2005 Apr;19(4):939-49. DOI:10.1210/me.2004-0443 |
- Rapaport D, Fichtman B, Weidberg H, Sprecher E, and Horowitz M. NEK3-mediated SNAP29 phosphorylation modulates its membrane association and SNARE fusion dependent processes. Biochem Biophys Res Commun. 2018 Mar 4;497(2):605-611. DOI:10.1016/j.bbrc.2018.02.116 |
