Inhibition of Centrosome Separation after DNA Damage: A Role for Nek2

Fletcher, Lynda; Cerniglia, George J.; Nigg, Erich A.; Yen, Tim J.; Muschel, Ruth J.

doi:10.1667/rr3211

Cited by 78 publications

(80 citation statements)

References 58 publications

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“…27 NEK2 promotes centrosome separation at the onset of mitosis and is involved in cell division and mitotic regulation. 47,48 Overexpression of NEK2 induces premature centrosome separation and nuclear defects, which are indicative of mitotic errors. 49 High levels of NEK2 expression are found in seminomas 27 and ductal carcinoma of the breast.…”

Section: Discussionmentioning

confidence: 99%

Expression profiling of 519 kinase genes in matched malignant peripheral nerve sheath tumor/plexiform neurofibroma samples is discriminatory and identifies mitotic regulators BUB1B, PBK and NEK2 as overexpressed with transformation

et al. 2013

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About 50% of all malignant peripheral nerve sheath tumors (MPNSTs) arise as neurofibromatosis type 1 associated lesions. In those patients malignant peripheral nerve sheath tumors are thought to arise through malignant transformation of a preexisting plexiform neurofibroma. The molecular changes associated with this transformation are still poorly understood. We sought to test the hypothesis that dysregulation of expression of kinases contributes to this malignant transformation. We analyzed expression of all 519 kinase genes in the human genome using the nanostring nCounter system. Twelve cases of malignant peripheral nerve sheath tumor arising in a background of preexisting plexiform neurofibroma were included. Both components were separately sampled. Statistical analysis compared global changes in expression levels as well as changes observed in the pairwise comparison of samples taken from the same surgical specimen. Immunohistochemical studies were performed on tissue array slides to confirm expression of selected proteins. The expression pattern of kinase genes can separate malignant peripheral nerve sheath tumors and preexisting plexiform neurofibromas. The majority of kinase genes is downregulated rather than overexpressed with malignant transformation. The patterns of expression changes are complex without simple recurring alteration. Pathway analysis demonstrates that differentially expressed kinases are enriched for kinases involved in the direct regulation of mitosis, and several of these show increased expression in malignant peripheral nerve sheath tumors. Immunohistochemical studies for the mitotic regulators BUB1B, PBK and NEK2 confirm higher expression levels at the protein level. These results suggest that the malignant transformation of plexiform neurofibroma is associated with distinct changes in the expression of kinase genes. The patterns of these changes are complex and heterogeneous. There is no single unifying alteration. Kinases involved in mitotic regulation are particularly enriched in the pool of differentially expressed kinases. Some of these are overexpressed and are therefore possible targets for kinase inhibitors.

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Section: Discussionmentioning

confidence: 99%

Expression profiling of 519 kinase genes in matched malignant peripheral nerve sheath tumor/plexiform neurofibroma samples is discriminatory and identifies mitotic regulators BUB1B, PBK and NEK2 as overexpressed with transformation

et al. 2013

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“…44). In addition, it was shown that cells exposed to ionizing radiation exhibit both decreased NEK2 expression and kinase activity, and exposure to ionizing radiation inhibits NEK2-mediated separation of the centrosome (45). Thus, p53-mediated repression of NEK2 could link centrosome inactivation to the DNA damage response network.…”

Section: Discussionmentioning

confidence: 99%

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

Nabilsi

Ryder

Peraza-Penton

et al. 2013

Journal of Biological Chemistry

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Background: NEK2 is a mammalian kinase that promotes centrosome separation during the cell cycle. Results: Agents that demethylate the NEK2 promoter or induce DNA damage repress NEK2 expression in a p53-dependent manner. Conclusion: p53 represses NEK2 expression and protects its binding region from accumulating DNA methylation. Significance: Knowledge regarding novel mechanisms of NEK2 regulation may help inform clinical application of NEK2-based anticancer therapeutics.

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“…AMPPNP, adenosine 5Ј-(␤,␥-imino)triphosphate. increase in apoptosis suggest that Nek2 may be a viable target for the development of novel anticancer drugs (39,40). We determined the structure of a non-activating Nek2 mutant in complex with the pyrrole-indolinone compound SU11652.…”

Section: Bacterial Expression Of Nek2 Constructs and Phosphorylationmentioning

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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Inhibition of Centrosome Separation after DNA Damage: A Role for Nek2

Cited by 78 publications

References 58 publications

Expression profiling of 519 kinase genes in matched malignant peripheral nerve sheath tumor/plexiform neurofibroma samples is discriminatory and identifies mitotic regulators BUB1B, PBK and NEK2 as overexpressed with transformation

Expression profiling of 519 kinase genes in matched malignant peripheral nerve sheath tumor/plexiform neurofibroma samples is discriminatory and identifies mitotic regulators BUB1B, PBK and NEK2 as overexpressed with transformation

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

Structure and Regulation of the Human Nek2 Centrosomal Kinase

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