Abstract
Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. Its activity is tightly regulated during the cell cycle with the help of other kinases and phosphatases and via proteasomal degradation. Increased levels of Nek2 kinase can promote centrosome amplification (CA), mitotic defects, chromosome instability (CIN), tumor growth, and cancer metastasis. While it remains a highly attractive target for the development of anti-cancer therapeutics, several new roles of the Nek2 enzyme have recently emerged: these include drug resistance, bone, ciliopathies, immune and kidney diseases, and parasitic diseases such as malaria. Therefore, Nek2 is at the interface of multiple cellular processes and can influence numerous cellular signaling networks. Herein, we provide a critical overview of Nek2 kinase biology and discuss the signaling roles it plays in both normal and diseased human physiology. While the majority of research efforts over the last two decades have focused on the roles of Nek2 kinase in tumor development and cancer metastasis, the signaling mechanisms involving the key players associated with several other notable human diseases are highlighted here. We summarize the efforts made so far to develop Nek2 inhibitory small molecules, illustrate their action modalities, and provide our opinion on the future of Nek2-targeted therapeutics. It is anticipated that the functional inhibition of Nek2 kinase will be a key strategy going forward in drug development, with applications across multiple human diseases.
Highlights
The human kinome represents the second most important class of therapeutic target after G-protein-coupled receptors (GPCRs)
This study showed that Nek2 overexpression led to activation of Akt signaling pathway, a finding discovered independently by our group [69]
Silencing of telomeric repeat binding factor 1 (TRF1) prevented mitotic failure; a rescue experiment in cells, consisting of the addition of exogenous TRF1 to Nek2-overexpressed cells with endogenous TRF1 depletion, re-induced cytokinetic failure. These results suggest that TRF1 is indispensable for overexpressed Nek2 to trigger abnormal mitosis and chromosomal instability (Figure 4) [92]
Summary
The human kinome represents the second most important class of therapeutic target after G-protein-coupled receptors (GPCRs). While as many as 76 protein kinase inhibitors are currently approved for clinical use by the United States Food and Drug Administration, several hundred are currently in the advanced stages of clinical development [2] These levels of success in clinics make kinases one of the most promising druggable targets. Nek primarily localizes at centrosomes and has been shown to regulate centrosome separation and bipolar spindle formation These two phenomena are central to mitotic chromosome segregation into two daughter cells; this is elegantly regulated by Nek kinase with extreme precision to achieve such a massive reorganization of cellular components. FFiigguurere1.1S.tSrutrcutucrtaul roarglaonrigzaatnioinzaoftitohne tohfretehseptlhicree-iesosfoprlmicseo-ifsNoefok2rmkinsaosfe Natethke2pkriimnaarsyesaetqtuheencperimary s lleevveel:l:NNeke2kA2,AN,eNk2eBk, 2anBd, aNnedk2NC.eTkh2eCth.rTeehiesothforremesidsiofffeorrsmigsnidfiicfafnetrlysaigt nthiefiircCan-ttelrymaintutshaenird Car-eterminu rreeppoortretdedtotpolapylacoyncteoxnt-tsepxetc-ifispc erocliefsi.c roles
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