NEK7 is required for G1 progression and procentriole formation

Gupta, Akshari; Tsuchiya, Yuki; Ohta, Masayuki; Shiratsuchi, Gen; Kitagawa, Daiju

doi:10.1091/mbc.e16-09-0643

Cited by 19 publications

(16 citation statements)

References 70 publications

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“…Indeed, similar phenotypes were generated by expression of a constitutively active NEK7, but not NEK6, kinase. These findings are consistent with growing evidence that NEK7 has microtubule-associated functions in interphase cells, with endogenous NEK7 localizing to the centrosome and depletion interfering with interphase microtubule dynamics, the centrosome duplication cycle and ciliogenesis 40,41,42,43,44 . Of particular interest to our findings, a kinasedependent role was recently described for NEK7 in stimulating dendrite growth in post-mitotic neurons.…”

Section: Discussionsupporting

confidence: 89%

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

O’Regan

Barone

Adib

et al. 2019

Preprint

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EML4-ALK is an oncogenic fusion present in ~5% lung adenocarcinomas. However, distinct EML4-ALK variants differ in the length of the EML4 microtubule-associated protein encoded within the fusion and are associated with a poorly understood variability in disease progression and therapeutic response. Here, we show that EML4-ALK variant 3, which is linked to accelerated metastatic spread and worse patient outcome, causes microtubule stabilization, formation of extended cytoplasmic protrusions, loss of cell polarity and increased cell migration. Strikingly, this is dependent upon the NEK9 kinase that interacts with the Nterminal region of EML4. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates cell migration in a manner that requires the downstream kinase NEK7 but not ALK activity. Moreover, elevated NEK9 is associated in patients with EML4-ALK V3 expression, as well as reduced progression-free and overall survival. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through recruitment of NEK9 and NEK7 to increase cell migration and that this represents a novel actionable pathway that drives disease progression in lung cancer.

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Section: Discussionsupporting

confidence: 89%

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

O’Regan

Barone

Adib

et al. 2019

Preprint

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“…However, this study did not find evidence for a role of NEK7 in centriole duplication, in contrast to previous studies ( Kim et al, 2011 ). However, in a recent study, a detailed investigation still showed the important impact of NEK7 depletion on contributions to centrosomal accumulation of the APC/C cofactor Cdh1, which negatively regulates centriole duplication ( Gupta et al, 2017 ). Later, RGS2 was reported to be a novel interactor of NEK7.…”

Section: Nek7 In the Regulation Of Mitosismentioning

confidence: 99%

Physiological and Pathological Roles of Mammalian NEK7

2020

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NEK7 is the smallest NIMA-related kinase (NEK) in mammals. The pathological and physiological roles of NEK7 have been widely reported in many studies. To date, the major function of NEK7 has been well documented in mitosis and NLRP3 inflammasome activation, but the detailed mechanisms of its regulation remain unclear. This review summarizes current advances in NEK7 research involving mitotic regulation, NLRP3 inflammasome activation, related diseases and potential inhibitors, which may provide new insights into the understanding and therapy of the diseases associated with NEK7, as well as the subsequent studies in the future.

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“…Indeed, both Nek6 and Nek7 are capable of directly phosphorylating microtubules in vitro (O'Regan and Fry, 2009 ). Furthermore, Nek6 and Nek7 have been implicated in regulation of centrosome duplication and maturation, senescence and the DNA damage response, all of which primarily take place in interphase (Lee et al, 2008 ; Jee et al, 2010 ; Kim et al, 2011 ; Gupta et al, 2017 ; Tan et al, 2017 ). Unexpectedly, Nek7 was found to be necessary for activation of the NLRP3 inflammasome, a multiprotein complex that activates inflammatory caspases in macrophages (He et al, 2016 ; Schmid-Burgk et al, 2016 ; Shi et al, 2016 ).…”

Section: Nek Kinases In Spindle Assemblymentioning

confidence: 99%

Mitotic Regulation by NEK Kinase Networks

Fry

Bayliss

Roig

2017

Front. Cell Dev. Biol.

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Genetic studies in yeast and Drosophila led to identification of cyclin-dependent kinases (CDKs), Polo-like kinases (PLKs) and Aurora kinases as essential regulators of mitosis. These enzymes have since been found in the majority of eukaryotes and their cell cycle-related functions characterized in great detail. However, genetic studies in another fungal species, Aspergillus nidulans, identified a distinct family of protein kinases, the NEKs, that are also widely conserved and have key roles in the cell cycle, but which remain less well studied. Nevertheless, it is now clear that multiple NEK family members act in networks to regulate specific events of mitosis, including centrosome separation, spindle assembly and cytokinesis. Here, we describe our current understanding of how the NEK kinases contribute to these processes, particularly through targeted phosphorylation of proteins associated with the microtubule cytoskeleton. We also present the latest findings on molecular events that control the activation state of the NEKs and how these are revealing novel modes of enzymatic regulation relevant not only to other kinases but also to pathological mechanisms of disease.

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NEK7 is required for G1 progression and procentriole formation

Cited by 19 publications

References 70 publications

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

Physiological and Pathological Roles of Mammalian NEK7

Mitotic Regulation by NEK Kinase Networks

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