CENPE

Official Full Name

centromere protein E

Organism

Homo sapiens

GeneID

1062

Background

Centrosome-associated protein E (CENPE) is a kinesin-like motor protein that accumulates in the G2 phase of the cell cycle. Unlike other centrosome-associated proteins, it is not present during interphase and first appears at the centromere region of chromosomes during prometaphase. This protein is required for stable spindle microtubule capture at kinetochores which is a necessary step in chromosome alignment during prometaphase. This protein also couples chromosome position to microtubule depolymerizing activity. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. [provided by RefSeq, Nov 2014]

Synonyms

KIF10; CENP-E; MCPH13; PPP1R61;

Bio Chemical Class

TRAFAC class myosin-kinesin ATPase

Protein Sequence

MAEEGAVAVCVRVRPLNSREESLGETAQVYWKTDNNVIYQVDGSKSFNFDRVFHGNETTKNVYEEIAAPIIDSAIQGYNGTIFAYGQTASGKTYTMMGSEDHLGVIPRAIHDIFQKIKKFPDREFLLRVSYMEIYNETITDLLCGTQKMKPLIIREDVNRNVYVADLTEEVVYTSEMALKWITKGEKSRHYGETKMNQRSSRSHTIFRMILESREKGEPSNCEGSVKVSHLNLVDLAGSERAAQTGAAGVRLKEGCNINRSLFILGQVIKKLSDGQVGGFINYRDSKLTRILQNSLGGNAKTRIICTITPVSFDETLTALQFASTAKYMKNTPYVNEVSTDEALLKRYRKEIMDLKKQLEEVSLETRAQAMEKDQLAQLLEEKDLLQKVQNEKIENLTRMLVTSSSLTLQQELKAKRKRRVTWCLGKINKMKNSNYADQFNIPTNITTKTHKLSINLLREIDESVCSESDVFSNTLDTLSEIEWNPATKLLNQENIESELNSLRADYDNLVLDYEQLRTEKEEMELKLKEKNDLDEFEALERKTKKDQEMQLIHEISNLKNLVKHAEVYNQDLENELSSKVELLREKEDQIKKLQEYIDSQKLENIKMDLSYSLESIEDPKQMKQTLFDAETVALDAKRESAFLRSENLELKEKMKELATTYKQMENDIQLYQSQLEAKKKMQVDLEKELQSAFNEITKLTSLIDGKVPKDLLCNLELEGKITDLQKELNKEVEENEALREEVILLSELKSLPSEVERLRKEIQDKSEELHIITSEKDKLFSEVVHKESRVQGLLEEIGKTKDDLATTQSNYKSTDQEFQNFKTLHMDFEQKYKMVLEENERMNQEIVNLSKEAQKFDSSLGALKTELSYKTQELQEKTREVQERLNEMEQLKEQLENRDSTLQTVEREKTLITEKLQQTLEEVKTLTQEKDDLKQLQESLQIERDQLKSDIHDTVNMNIDTQEQLRNALESLKQHQETINTLKSKISEEVSRNLHMEENTGETKDEFQQKMVGIDKKQDLEAKNTQTLTADVKDNEIIEQQRKIFSLIQEKNELQQMLESVIAEKEQLKTDLKENIEMTIENQEELRLLGDELKKQQEIVAQEKNHAIKKEGELSRTCDRLAEVEEKLKEKSQQLQEKQQQLLNVQEEMSEMQKKINEIENLKNELKNKELTLEHMETERLELAQKLNENYEEVKSITKERKVLKELQKSFETERDHLRGYIREIEATGLQTKEELKIAHIHLKEHQETIDELRRSVSEKTAQIINTQDLEKSHTKLQEEIPVLHEEQELLPNVKEVSETQETMNELELLTEQSTTKDSTTLARIEMERLRLNEKFQESQEEIKSLTKERDNLKTIKEALEVKHDQLKEHIRETLAKIQESQSKQEQSLNMKEKDNETTKIVSEMEQFKPKDSALLRIEIEMLGLSKRLQESHDEMKSVAKEKDDLQRLQEVLQSESDQLKENIKEIVAKHLETEEELKVAHCCLKEQEETINELRVNLSEKETEISTIQKQLEAINDKLQNKIQEIYEKEEQFNIKQISEVQEKVNELKQFKEHRKAKDSALQSIESKMLELTNRLQESQEEIQIMIKEKEEMKRVQEALQIERDQLKENTKEIVAKMKESQEKEYQFLKMTAVNETQEKMCEIEHLKEQFETQKLNLENIETENIRLTQILHENLEEMRSVTKERDDLRSVEETLKVERDQLKENLRETITRDLEKQEELKIVHMHLKEHQETIDKLRGIVSEKTNEISNMQKDLEHSNDALKAQDLKIQEELRIAHMHLKEQQETIDKLRGIVSEKTDKLSNMQKDLENSNAKLQEKIQELKANEHQLITLKKDVNETQKKVSEMEQLKKQIKDQSLTLSKLEIENLNLAQKLHENLEEMKSVMKERDNLRRVEETLKLERDQLKESLQETKARDLEIQQELKTARMLSKEHKETVDKLREKISEKTIQISDIQKDLDKSKDELQKKIQELQKKELQLLRVKEDVNMSHKKINEMEQLKKQFEAQNLSMQSVRMDNFQLTKKLHESLEEIRIVAKERDELRRIKESLKMERDQFIATLREMIARDRQNHQVKPEKRLLSDGQQHLTESLREKCSRIKELLKRYSEMDDHYECLNRLSLDLEKEIEFQKELSMRVKANLSLPYLQTKHIEKLFTANQRCSMEFHRIMKKLKYVLSYVTKIKEEQHESINKFEMDFIDEVEKQKELLIKIQHLQQDCDVPSRELRDLKLNQNMDLHIEEILKDFSESEFPSIKTEFQQVLSNRKEMTQFLEEWLNTRFDIEKLKNGIQKENDRICQVNNFFNNRIIAIMNESTEFEERSATISKEWEQDLKSLKEKNEKLFKNYQTLKTSLASGAQVNPTTQDNKNPHVTSRATQLTTEKIRELENSLHEAKESAMHKESKIIKMQKELEVTNDIIAKLQAKVHESNKCLEKTKETIQVLQDKVALGAKPYKEEIEDLKMKLVKIDLEKMKNAKEFEKEISATKATVEYQKEVIRLLRENLRRSQQAQDTSVISEHTDPQPSNKPLTCGGGSGIVQNTKALILKSEHIRLEKEISKLKQQNEQLIKQKNELLSNNQHLSNEVKTWKERTLKREAHKQVTCENSPKSPKVTGTASKKKQITPSQCKERNLQDPVPKESPKSCFFDSRSKSLPSPHPVRYFDNSSLGLCPEVQNAGAESVDSQPGPWHASSGKDVPECKTQ

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

Discontinued Drug

1 +

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Detailed Information

In the G2 phase of the cell cycle, Centrosome-associated protein E (CENPE) accumulates as a kinesin-like motor protein and first appears in the centromere region during prometaphase. Unlike other centrosome-associated proteins, CENPE is absent during interphase. A core function of CENPE is to promote chromosome alignment during prometaphase by stabilizing the attachment of spindle microtubules to kinetochores. Additionally, CENPE connects the position of chromosomes with microtubule depolymerizing activities. This protein is expressed through multiple transcript variants resulting from alternative splicing, thus encoding distinct isoforms.

Structural Features and Functional Mechanism of CENPE

CENPE is composed of an N-terminal motor domain, a central coiled-coil domain, and a C-terminal tail domain. The N-terminal motor domain is highly conserved across various organisms. Unlike conventional kinesins, CENPE possesses a 230-nanometer-long discontinuous coiled coil that can form different conformations in vitro and carry cargo in a compact configuration. The long coiled-coil domain supports the motor function and structural flexibility of CENPE. The adjustable stalk configuration is crucial for CENPE's physical interactions with spindle microtubules.

Figure 1: The structure and molecular kinetics of kinesin-7 CENP-E include distinct domains for motility and binding, with a motor domain facilitating movement, and a coiled-coil domain enabling dimerization and interactions. Figure 1. Structure and molecular kinetics of kinesin-7 CENP-E. (Yang YH., et al., 2024)

Full-length human CENPE becomes active upon microtubule binding, allowing it to move to the plus end of microtubules and remain at the microtubule end for approximately 20 seconds. Its tail domain comprises targeting regions for kinetochores, centrosomes, and microtubules, critical for its specific binding to spindle microtubules. The tail domain also can inhibit CENPE's motor activity through motor-tail interactions.

During cell division in mammalian cells, kinetochore fibers are composed of 20 to 30 microtubules, which are essential for end-on attachment between microtubule plus ends and kinetochores. During mitosis, CENPE proteins accumulate on unattached and misaligned kinetochores during prometaphase and dissociate from aligned kinetochores during metaphase. Research indicates that CENPE is released from an autoinhibited state through phosphorylation by Aurora A and B kinases, with Aurora B phosphorylating CENPE at kinetochores to prevent premature removal by dynein.

Expression Patterns of CENPE in Cancer

The high-level expression of CENPE is closely linked to its essential roles in cell division. Among the many malignancies CENPE is elevated in: neuroblastoma, retinoblastoma, melanoma, esophageal cancer, lung adenocarcinoma, gliomas, non-small cell lung cancer, basal-like breast cancer, chemotherapy-resistant epithelial ovarian cancer, and castration-resistant prostate cancer. Furthermore shown by studies employing TCGA, GEPIA, and Oncomine databases include elevated CENPE gene expression in many tumor types, including colorectal cancer, cervical cancer, gastric cancer, breast cancer, lung cancer, and sarcoma.

In breast cancer cells, poor prognosis is linked to overexpression of the CENPE gene. The higher expression of CENPE improves the susceptibility of breast tumors to the medication (+)—JQ1. Moreover, low general survival in individuals with esophageal cancer and adenocarcinoma corresponds with the strong expression of the CENPE gene. High CENPE expression in retinoblastoma cell lines is favorably correlated with tumor cell invasiveness, suggesting a possible function as a biomarker and therapeutic target.

Disease Relevance and Treatment

Participating in the stability of kinetochore-microtubule attachments and the activation of the spindle assembly checkpoint, CENPE helps to avoid chromosomal missegregation and aneuploidy, therefore playing a vital function in the mitotic checkpoint and cell cycle regulation. Key controllers of cell division, the kinesin family motors—including CENPE—have grown to be possible targets for chemotherapeutic intervention and cancer therapy. Synthetic-specific inhibitors of CENPE have been developed and confirmed; GSK923295 is now under trial Phase I. Together with the uses of its inhibitors, the link between CENPE and carcinogenesis offers a fresh angle for cancer research and therapy.

CENPE's unique functions during chromosomal alignment and transition in cell division highlight its potential as a target in cancer therapy. Inhibition of CENPE through siRNA or GSK923295 activates TP53 or TP73 and cell death signaling pathways, indicating that CENPE may be a potential therapeutic target for medulloblastoma.

References:

Craske B, Welburn JPI. Leaving no-one behind: how CENP-E facilitates chromosome alignment. Essays Biochem. 2020 Sep 4;64(2):313-324.
Yu KW, Zhong N, et al. Mechanisms of kinesin-7 CENP-E in kinetochore-microtubule capture and chromosome alignment during cell division. Biol Cell. 2019 Jun;111(6):143-160.
Yang YH, Wei YL, et al. Kinesin-7 CENP-E in tumorigenesis: Chromosome instability, spindle assembly checkpoint, and applications. Front Mol Biosci. 2024;11:1366113.

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