NEK8

NEK8 (NIMA-related kinase 8) is a serine/threonine kinase of the NIMA kinase family that localizes to primary cilia and the ciliary inversin (INV) compartment, where it contributes to organ development and cilia-dependent signaling processes^[1][2]. NEK8 functions within protein complexes containing ANKS6, INVS, and NPHP3, and is required for proper left-right patterning, renal tubular integrity, and maintenance of ciliary architecture^[1][3]. Mechanistically, NEK8 extends beyond classical ciliary functions by acting as a regulator of the ATR-mediated replication stress response, where it controls replication fork dynamics, limits aberrant S-phase CDK activity, and suppresses DNA damage accumulation^[4]. Therefore, NEK8 provides a molecular link between ciliary signaling and genome maintenance pathways that are critical for epithelial tissue homeostasis^[4]. In disease settings, pathogenic NEK8 variants are associated with nephronophthisis, polycystic kidney disease, and severe renal-hepatic-pancreatic dysplasia, with affected cells displaying defects in ciliary localization, epithelial morphogenesis, and developmental signaling^[2][5][6]. Altered Hippo pathway activity, including dysregulation of YAP/TAZ-dependent transcriptional programs, has been reported in multiple NEK8-associated developmental disorders, further supporting its role in organogenesis and cystic disease pathogenesis^[5][6]. Compared with the closely related kinase NEK9, NEK8 possesses a specialized ciliary localization and functions predominantly within the INV compartment rather than as a canonical G2/M mitotic regulator, highlighting a distinct biological role among NIMA-family kinases^[1]. Currently, no selective NEK8-targeted agonists or inhibitors are established for routine experimental use, and research applications primarily rely on genetic perturbation models to investigate ciliopathy mechanisms, DNA damage responses, and developmental signaling networks^[1].