Never say never. The NIMA-related protein kinases in mitotic control

O’Connell, Matthew J.; Krien, Michael J.E.; Hunter, Tony

doi:10.1016/s0962-8924(03)00056-4

Cited by 213 publications

(195 citation statements)

References 62 publications

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“…However, it is tempting to speculate that in both cases the microtubule network is affected. The involvement of NIMA-related kinases in microtubule control has long been suspected (O'Connell et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…One possible target is the microtubule network as several studies demonstrate the involvement of NIMA kinases in microtubule-related activities (O'Connell et al, 2003;O'Regan et al, 2007). In addition, Nek6 and Nek7 were localized to the centrosome and the mitotic spindle (Yissachar et al, 2006;Kim et al, 2007;O'Regan and Fry, 2009), Nek7 deregulation was reported to affect microtubule nucleation (Kim et al, 2007), and Nek6 and Nek7 bind and phosphorylate microtubule preparations, at least in vitro (O'Regan and Fry, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…As implied by its name ('never in mitosis A'), NIMA activity is vital for fungal cells to overstep the G2/M checkpoint and to enter mitosis. The NIMA protein has been shown to be implicated in chromatin condensation, cell division cycle 2/cyclin B localization and microtubule network dynamics (Fry and Nigg, 1995;De Souza et al, 2003;O'Connell et al, 2003). The mammalian genome has 11 NIMA-related kinases, designated Nek1-11 (O'Connell et al, 2003;O'Regan et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

et al. 2010

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The mammalian NIMA-related kinases (Neks) are commonly referred to as mitotic kinases, although a definitive in vivo verification of this definition is largely missing. Reduction in the activity of Nek7 or its close paralog, Nek6, has previously been shown to arrest cells in mitosis, mainly at metaphase. In this study, we investigate the developmental and cellular roles of Nek7 kinase through the generation and analysis of Nek7-deficient mice. We show that absence of Nek7 leads to lethality in late embryogenesis or at early post-natal stages and to severe growth retardation. Mouse embryonic fibroblasts (MEFs) derived from Nek7 À/À embryos show increase tendency for chromosomal lagging, micronuclei formation and cytokinesis failure. Tetraploidy and aneuploidy were commonly observed and their prevalence arises with MEFs passages. The frequency of multicentrosomal cells in the mutant's MEF cells was higher, and it commonly occurred concurrently with a binuclear phenotype, suggesting cytokinesis failure etiology. Lastly, the percentage of mutant MEF cells bearing primary cilia (PC) was low, whereas a cell population having two cilia appeared in the mutant MEFs. Taken together, these results confirm Nek7 as a regulator of cell division, and reveal it as an essential component for mammalian growth and survival. The intimate connection between tetraploidy, aneuploidy and cancer development suggests that Nek7 deregulation can induce oncogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

et al. 2010

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“…Although the yeast Neks do not appear to be essential for cell cycle progression, elegant studies on Fin1 have revealed key functions in chromosome segregation and mitotic exit (3,4). In contrast, higher eukaryotes express multiple Neks with 11 genes (Nek1 to Nek11) encoded within the human genome (1). With the exception of human Nek6 and Nek7 and Nek10, all Neks have an N-terminal kinase domain followed by a C-terminal non-catalytic regulatory domain.…”

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confidence: 99%

Structure and Regulation of the Human Nek2 Centrosomal Kinase

Rellos

Ivins

Baxter

et al. 2007

Journal of Biological Chemistry

125

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The dimeric Ser/Thr kinase Nek2 regulates centrosome cohesion and separation through phosphorylation of structural components of the centrosome, and aberrant regulation of Nek2 activity can lead to aneuploid defects characteristic of cancer cells. Mutational analysis of autophosphorylation sites within the kinase domain identified by mass spectrometry shows a complex pattern of positive and negative regulatory effects on kinase activity that are correlated with effects on centrosomal splitting efficiency in vivo. The 2.2-Å resolution x-ray structure of the Nek2 kinase domain in complex with a pyrrole-indolinone inhibitor reveals an inhibitory helical motif within the activation loop. This helix presents a steric barrier to formation of the active enzyme and generates a surface that may be exploitable in the design of specific inhibitors that selectively target the inactive state. Comparison of this "auto-inhibitory" conformation with similar arrangements in cyclin-dependent kinase 2 and epidermal growth factor receptor kinase suggests a role for dimerization-dependent allosteric regulation that combines with autophosphorylation and protein phosphatase 1c phosphatase activity to generate the precise spatial and temporal control required for Nek2 function in centrosomal maturation.Protein kinase activity is crucial for the precise regulation of the eukaryotic cell cycle. Although cyclin-dependent kinases remain the master regulators of cell cycle progression, it is clear that a variety of other proteins kinases also play important roles.Nek2 is a member of the NIMA 6 -related kinase (or Nek) family of serine/threonine protein kinases, so named because all are related to the NIMA kinase of Aspergillus nidulans (for review, see Ref. 1). In Aspergillus, NIMA is essential for mitotic entry with temperature-sensitive nimA mutations leading to cells that are "never in mitosis" (2). Like Aspergillus, other fungi also express a single NIMA-related kinase, e.g. Kin3 in Saccharomyces cerevisiae and Fin1 in Schizosaccharomyces pombe. Although the yeast Neks do not appear to be essential for cell cycle progression, elegant studies on Fin1 have revealed key functions in chromosome segregation and mitotic exit (3, 4). In contrast, higher eukaryotes express multiple Neks with 11 genes (Nek1 to Nek11) encoded within the human genome (1). With the exception of human Nek6 and Nek7 and Nek10, all Neks have an N-terminal kinase domain followed by a C-terminal non-catalytic regulatory domain. However, the length and composition of motifs present within these C-terminal extensions vary considerably, reflecting diverse roles in cell regulation.Of the human proteins, Nek2 is the most closely related to the fungal kinases, being 47% identical to NIMA within the amino acid sequence of their catalytic domains. Nek2 localizes to centrosomes. Here, it contributes to spindle pole formation during mitosis (5) through phosphorylation of proteins involved in centriolar cohesion, including C-Nap1 and rootletin, to allow spindle pole separation (6 ...

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“…Protein kinases structurally related to fungal NIMA have been identified in various organisms (2). In the human genome, eleven NIMArelated kinases (Nek1-11) have been reported (3).…”

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confidence: 99%

Nucleolar Nek11 Is a Novel Target of Nek2A in G1/S-arrested Cells

Noguchi

Fukazawa

Murakami

et al. 2004

Journal of Biological Chemistry

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We previously reported that Nek11, a member of the NIMA (never-in-mitosis A) family of kinases, is activated in G 1 /S-arrested cells. We provide herein several lines of evidence for a novel interaction between Nek11 and Nek2A. Both Nek11 and Nek2A, but not Nek2B, were detected at nucleoli, and the Nek2A-specific C-terminal end (amino acids 399 -445) was responsible for nucleolar localization. Endogenous Nek11 coimmunoprecipitated with endogenous Nek2A, and non-catalytic regions of each kinase were involved in the complex formation. Nek11L interacted with phosphorylated Nek2A but barely with the kinase-inactive Nek2A (K37R) mutant. In addition, both Nek2A autophosphorylation activity and the Nek11L-Nek2A complex formation increased in G 1 /S-arrested cells. These results indicate that autophosphorylation of Nek2A could stimulate its interaction with Nek11L at the nucleolus. Moreover, Nek2 directly phosphorylated Nek11 in the C-terminal noncatalytic region and elevated Nek11 kinase activity. The non-catalytic region of Nek11 showed autoinhibitory activity through intramolecular interaction with its N-terminal catalytic domain. Nek2 dissociated this autoinhibitory interaction. Altogether, our studies demonstrate a unique mechanism of Nek11 activation by Nek2A in G 1 /S-arrested cells and suggest a novel possibility for nucleolar function of the NIMA family.The NIMA 1 (never-in mitosis A) kinase was first identified in the filamentous fungus Aspergillus nidulans by genetic complementation of the nimA mutation and is essential for nuclear division cycle at G 2 /M transition (1). Protein kinases structurally related to fungal NIMA have been identified in various organisms (2). In the human genome, eleven NIMArelated kinases (Nek1-11) have been reported (3).In human, Nek2, the most fungal NIMA-related kinase, is the best characterized (4). Two splice variants of Nek2, Nek2A and Nek2B that encode different C termini have been identified (5, 6). Non-catalytic C-terminal region of Nek2A but not that of Nek2B has the PP1 binding domain (6). PP1 represses Nek2A autophosphorylation and activation by dephosphorylation (7). Both Nek2A and Nek2B are cell cycle-regulated protein kinases detected at the centrosome (6), and Nek2A overexpression causes premature centrosome splitting (8). Although the role of Nek2B is unclear in somatic cells, Nek2B has an important function in zygotic centrosome assembly and maintenance in Xenopus oocytes (9 -11). The studies on NIMArelated kinases in lower organisms also support a model that the regulatory function in the spindle pole body/microtubules organization center/centrosome is a conserved activity of Nek2-like kinases (12, 13). Additionally, Nek2 could localize at nucleus in somatic cell lines albeit its physiological significance remains (8,14), and the functional significance of Nek2A specific extra coiled-coil domain at the C-terminal end has not been addressed. Concerning other member of human Neks, most of their functions have been largely unclear; however, recent studies are beginn...

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Never say never. The NIMA-related protein kinases in mitotic control

Cited by 213 publications

References 62 publications

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

Structure and Regulation of the Human Nek2 Centrosomal Kinase

Nucleolar Nek11 Is a Novel Target of Nek2A in G1/S-arrested Cells

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