NEK2

Official Full Name

NIMA related kinase 2

Organism

Homo sapiens

GeneID

4751

Background

This gene encodes a serine/threonine-protein kinase that is involved in mitotic regulation. This protein is localized to the centrosome, and undetectable during G1 phase, but accumulates progressively throughout the S phase, reaching maximal levels in late G2 phase. Alternatively spliced transcript variants encoding different isoforms with distinct C-termini have been noted for this gene. [provided by RefSeq, Feb 2011]

Synonyms

NLK1; RP67; NEK2A; HsPK21; PPP1R111;

Bio Chemical Class

Kinase

Protein Sequence

MPSRAEDYEVLYTIGTGSYGRCQKIRRKSDGKILVWKELDYGSMTEAEKQMLVSEVNLLRELKHPNIVRYYDRIIDRTNTTLYIVMEYCEGGDLASVITKGTKERQYLDEEFVLRVMTQLTLALKECHRRSDGGHTVLHRDLKPANVFLDGKQNVKLGDFGLARILNHDTSFAKTFVGTPYYMSPEQMNRMSYNEKSDIWSLGCLLYELCALMPPFTAFSQKELAGKIREGKFRRIPYRYSDELNEIITRMLNLKDYHRPSVEEILENPLIADLVADEQRRNLERRGRQLGEPEKSQDSSPVLSELKLKEIQLQERERALKAREERLEQKEQELCVRERLAEDKLARAENLLKNYSLLKERKFLSLASNPELLNLPSSVIKKKVHFSGESKENIMRSENSESQLTSKSKCKDLKKRLHAAQLRAQALSDIEKNYQLKSRQILGMR

Open

Approved Drug

Clinical Trial Drug

Discontinued Drug

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Detailed Information

Nek2 is a member of the NIMA-associated protein kinase family and is a special chromosomalin-function (CIN) gene. The Nek2 protein is a key protein regulating mitosis and plays an important role in centrosome separation, spindle formation and mitosis.

Figure 1. Model of the roles of Nek2 in cilia biogenesis and resorption. (Endicott, S. J., et al. 2015)

The Features of Nek2

Nek2 is highly similar to NIMA in the catalytic region, except that Nek2 is not required for cells to enter the mitotic process. Its main role in this process is to regulate the separation of the centrosome. The study found that Nek2 in mammals mainly regulates the centrosomes from G2 to M to the two poles, which plays an important role in the formation of bipolar spindles and the isolation of chromosomes. The complex of Nek2 and protein phosphatase1 (PP) 1 is one of the main regulators of centrosome adhesion and separation, which ensures the smooth entry of the G2 spindle into the M phase. Nek2 is inhibited by PP1 during cell mitosis, and its activity is low. In the late G2 phase, PP1 is gradually inactivated or displaced, resulting in inhibition of Nek2 and increased activity to promote centrosome separation. During the regulation, Nek2 mainly connects two proteins of two unseparated centrosomes by phosphorylation, that is, the centrosome-associated protein 1 and the small root protein are linked to separate them from the central body. Therefore, the expression of Nek2 is increased or the activity is increased, and the inhibition of PP1 and centrosome-associated protein 1 promotes the separation of centrosomes.

In addition to regulating the central body, Nek2 also promotes chromatin condensation and separation of intermediates from histone H3 cells at the centromere, and plays an important role in the accurate separation of chromosomes. The key to Nek2's function is the phosphorylation of cancer-producing proteins. Non-phosphorylated high-expression proteins in cancer interfere with the concentration of chromatin and can cause widespread errors in the adhesion of microtubules to centromeres, which can cause monopolar or multipolar adhesion. Therefore, only phosphorylated cancer-expressed proteins can ensure accurate chromosome segregation.

Nek2 and Tumor

Studies have found that aberrantly expressed Nek2 binds to and further phosphorylates Mad2 and Cdc20, so as to interfere with their role as checkpoints during mitosis, leading to host chromosomal instability leading to tumorigenesis. Studies have shown that overexpression of active Nek2A leads to early differentiation of immature centrosomes, while inactive Nek2A overexpression results in abnormal centrosomes including monopolar spindles and non-integer ploidy. Studies have also found that the expression of Nek2 gene levels is significantly up-regulated in human testicular seminoma. The expression of Nek2 in breast carcinoma in situ and breast invasive carcinoma was significantly higher than that in normal breast tissue, but it was significantly higher in breast invasive carcinoma than in breast carcinoma in situ. Studies have revealed that the mRNA and protein levels of Nek2 expressed by human cholangiocarcinoma cells are significantly higher than those of normal fibroblasts. Nek2 not only participates in centrosome separation, but also participates in chromatin condensation and chromosome segregation. Therefore, Nek2 can indirectly regulate centrosomes and directly interfere with chromosomes to affect the stability of the entire mitotic process, thereby promoting the transformation of cells into malignant hyperplasia. Increased expression and activity of Nek2 is the most common form of expression in tumor cells.

References:

Endicott, S. J. , Basu, B. , Khokha, M. , & Brueckner, M. . (2015). The nima-like kinase nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry. Development, dev.126953.
Kaowinn, S. , Oh, S. , Moon, J. , Yoo, A. Y. , Kang, H. Y. , & Lee, M. R. , et al. (2019). Cgk062, a small chemical molecule, inhibits cancer upregulated gene 2‑induced oncogenesis through nek2 and β‑catenin. International Journal of Oncology.
Wang, X. , Chen, K. , Liu, H. , Huang, Z. , Chen, X. , & Yin, L. . (2018). Prognostic significance of nek2 in human solid tumors: a systematic review and meta-analysis. Bioscience Reports.

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