The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry

Endicott, S. Joseph; Basu, Basudha; Khokha, Mustafa K.; Brueckner, Martina

doi:10.1242/dev.126953

Cited by 30 publications

(30 citation statements)

References 67 publications

(103 reference statements)

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“…The authors observed that the cilia and motile cilia counts were in nek2 morphants and hNEK2 overexpressors. Additionally, NEK2 overexpression promotes increased cilia resorption by phosphorylation of Nup98 [24].…”

Section: Nek2mentioning

confidence: 99%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.

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Section: Nek2mentioning

confidence: 99%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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“…The cilium's permeability barrier is also characterized by the presence of Nups, including FG-containing Nups [22,31], and has thus been termed the ciliary pore complex (CPC, Figure 2). To study the function of FG-containing Nups in gated entry, Takao et al developed a “pore clogging assay” by rapid and specific crosslinking of the central channel nucleoporin Nup62 [32**].…”

Section: Generating a Unique Luminal Protein Compositionmentioning

confidence: 99%

Permeability barriers for generating a unique ciliary protein and lipid composition

Verhey

Yang

2016

Current Opinion in Cell Biology

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Cilia (and flagella) are microtubule-based protrusions that are found in single or multiple copies on the surface of most eukaryotic cells. Defects in cilia formation and/or function have now been correlated with an expanding spectrum of human genetic diseases termed ciliopathies. Recent work indicates that cilia are indeed a bona fide organelle with a unique protein and lipid content that enables specific cellular functions. Despite the physiological and clinical relevance of cilia, our understanding of how a unique protein and lipid composition is generated for this organelle remains poor. Here we review recent work on the mechanisms that determine the protein and lipid content, and thus the functional outputs, of this unique organelle.

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“…Nek2 controls cilia disassembly; depletion of Nek2 causes an increase in the number of ciliated cells [ 8 ]. Nek2 has been linked directly to disruption of left-right asymmetry, a biological consequence of cilia dysfunction [ 10 ]. Nek2 also regulates intraflagellar transport (IFT) through phosphorylation of the kinesin KIF24 to stimulate cilia depolymerization [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

A novel interaction between kinase activities in regulation of cilia formation

et al. 2017

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BackgroundThe primary cilium is an extension of the cell membrane that encloses a microtubule-based axoneme. Primary cilia are essential for transmission of environmental cues that determine cell fate. Disruption of primary cilia function is the molecular basis of numerous developmental disorders. Despite their biological importance, the mechanisms governing their assembly and disassembly are just beginning to be understood. Cilia growth and disassembly are essential events when cells exit and reenter into the cell cycle. The kinases never in mitosis-kinase 2 (Nek2) and Aurora A (AurA) act to depolymerize cilia when cells reenter the cell cycle from G0.ResultsCoexpression of either kinase with its kinase dead companion [AurA with kinase dead Nek2 (Nek2 KD) or Nek2 with kinase dead AurA (AurA KD)] had different effects on cilia depending on whether cilia are growing or shortening. AurA and Nek2 are individually able to shorten cilia when cilia are growing but both are required when cilia are being absorbed. The depolymerizing activity of each kinase is increased when coexpressed with the kinase dead version of the other kinase but only when cilia are assembling. Additionally, the two kinases act additively when cilia are assembling but not disassembling. Inhibition of AurA increases cilia number while inhibition of Nek2 significantly stimulates cilia length. The complex functional relationship between the two kinases reflects their physical interaction. Further, we identify a role for a PP1 binding protein, PPP1R42, in inhibiting Nek2 and increasing ciliation of ARPE-19 cells.ConclusionWe have uncovered a novel functional interaction between Nek2 and AurA that is dependent on the growth state of cilia. This differential interdependence reflects opposing regulation when cilia are growing or shortening. In addition to interaction between the kinases to regulate ciliation, the PP1 binding protein PPP1R42 directly inhibits Nek2 independent of PP1 indicating another level of regulation of this kinase. In summary, we demonstrate a complex interplay between Nek2 and AurA kinases in regulation of ciliation in ARPE-19 cells.Electronic supplementary materialThe online version of this article (10.1186/s12860-017-0149-5) contains supplementary material, which is available to authorized users.

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The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry

Cited by 30 publications

References 67 publications

Checking NEKs: Overcoming a Bottleneck in Human Diseases

Checking NEKs: Overcoming a Bottleneck in Human Diseases

Permeability barriers for generating a unique ciliary protein and lipid composition

A novel interaction between kinase activities in regulation of cilia formation

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