PLK1

Official Full Name

polo like kinase 1

Organism

Homo sapiens

GeneID

5347

Background

The Ser/Thr protein kinase encoded by this gene belongs to the CDC5/Polo subfamily. It is highly expressed during mitosis and elevated levels are found in many different types of cancer. Depletion of this protein in cancer cells dramatically inhibited cell proliferation and induced apoptosis; hence, it is a target for cancer therapy. [provided by RefSeq, Sep 2015]

Synonyms

PLK; STPK13;

Bio Chemical Class

Kinase

Protein Sequence

MSAAVTAGKLARAPADPGKAGVPGVAAPGAPAAAPPAKEIPEVLVDPRSRRRYVRGRFLGKGGFAKCFEISDADTKEVFAGKIVPKSLLLKPHQREKMSMEISIHRSLAHQHVVGFHGFFEDNDFVFVVLELCRRRSLLELHKRRKALTEPEARYYLRQIVLGCQYLHRNRVIHRDLKLGNLFLNEDLEVKIGDFGLATKVEYDGERKKTLCGTPNYIAPEVLSKKGHSFEVDVWSIGCIMYTLLVGKPPFETSCLKETYLRIKKNEYSIPKHINPVAASLIQKMLQTDPTARPTINELLNDEFFTSGYIPARLPITCLTIPPRFSIAPSSLDPSNRKPLTVLNKGLENPLPERPREKEEPVVRETGEVVDCHLSDMLQQLHSVNASKPSERGLVRQEEAEDPACIPIFWVSKWVDYSDKYGLGYQLCDNSVGVLFNDSTRLILYNDGDSLQYIERDGTESYLTVSSHPNSLMKKITLLKYFRNYMSEHLLKAGANITPREGDELARLPYLRTWFRTRSAIILHLSNGSVQINFFQDHTKLILCPLMAAVTYIDEKRDFRTYRLSLLEEYGCCKELASRLRYARTMVDKLLSSRSASNRLKAS

Open

Disease

Acute myeloid leukaemia, Lymphoma, Malignant haematopoietic neoplasm, Myelodysplastic syndrome, Nasopharyngeal cancer, Pancreatic cancer, Prostate cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

12 +

Discontinued Drug

1 +

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Detailed Information

Polo-like kinase 1 (PLK1) encodes a highly conserved serine/threonine kinase and belongs to the CDC5/Polo kinase subfamily. The human PLK1 gene is located on chromosome 16p12.1, contains ten exons, and encodes a protein of 603 amino acids with a molecular weight of approximately 66 kDa. PLK1 has a bipartite structure composed of an N-terminal kinase domain and a C-terminal polo-box domain (PBD). The kinase domain catalyzes substrate phosphorylation, while the PBD mediates protein–protein interactions and subcellular localization by recognizing phosphorylated serine/threonine motifs. PLK1 expression is tightly cell cycle–dependent, peaking at the G2/M phase and nearly absent in G1, under dual control of transcriptional regulation and ubiquitin–proteasome degradation.

Figure 1. Domain structure of PLK1. (Liu Z, et al., 2017)

Molecular Mechanisms of Regulation

Mechanistically, PLK1 recognizes primed substrates pre-phosphorylated by CDKs and other “initiator kinases” through its PBD and then completes full phosphorylation, a two-step activation mechanism that ensures precise control of downstream signaling. Its catalytic activity is further regulated by phosphorylation of Thr210 within the activation loop, which is critical for full activation. This multilayered regulation allows PLK1 to orchestrate key mitotic events with spatiotemporal precision, from centrosome maturation and spindle assembly to kinetochore–microtubule attachment, chromosome segregation, and cytokinesis.

Biological Functions and Epigenetic Roles

Beyond its classical role in mitosis, PLK1 has recently been linked to epigenetic regulation. It phosphorylates the chromatin regulator UHRF1 at Ser265, enhancing its interaction with USP7 and stabilizing UHRF1 protein levels, which in turn maintains DNA methylation patterns through DNMT1 recruitment. Inhibition of PLK1 destabilizes UHRF1, reduces DNMT1 binding to chromatin, lowers global DNA methylation, and reactivates tumor suppressor genes such as p16 and p21, thereby suppressing tumor proliferation. This PLK1–UHRF1–DNMT1 axis provides new mechanistic insight into the anticancer effects of PLK1 inhibitors.

Role in Cancer Development

Overexpression of PLK1 promotes chromosomal instability and aneuploidy, which are strongly correlated with poor prognosis and therapy resistance. In prostate cancer, particularly under PTEN loss, PLK1 is critical for mitotic survival, and its inhibition selectively induces apoptosis in tumor cells. In acute myeloid leukemia (AML), PLK1 overexpression contributes to resistance against FLT3 inhibitors by modulating the FLT3/STAT5/ERK/mTOR pathway, while combined targeting of PLK1 and FLT3 signaling has shown synergistic therapeutic effects in preclinical models.

Clinical Research and Therapeutic Potential

Several PLK1 inhibitors, such as BI 2536, volasertib (BI 6727), GSK461364, and ON 01910, have entered clinical trials. Volasertib demonstrated encouraging efficacy in AML phase II studies when combined with low-dose cytarabine, though subsequent phase III trials were limited by dose-dependent toxicities, highlighting the need for improved selectivity and delivery systems. Combination therapy strategies appear particularly promising: PLK1 inhibitors can synergize with chemotherapy or epigenetic drugs by reversing tumor suppressor gene silencing, and metabolic agents such as metformin have been shown to enhance sensitivity to FLT3 inhibitors through PLK1 modulation.

Summary and Future Perspectives

PLK1 is a central regulator of the cell cycle whose functions extend into epigenetic and metabolic reprogramming. Its dysregulation drives multiple aspects of tumorigenesis, and its inhibition has shown therapeutic potential across hematological and solid malignancies. Future directions focus on the development of highly selective inhibitors, exploration of predictive biomarkers such as UHRF1 phosphorylation and DNA methylation signatures, and rational design of combination therapies that integrate cytotoxic, epigenetic, targeted, and immunotherapeutic approaches. By serving as a critical hub linking cell cycle progression, DNA repair, and epigenetic regulation, PLK1 remains a compelling target for next-generation cancer therapies.

Reference

Liu Z, Sun Q, Wang X. PLK1, A Potential Target for Cancer Therapy. Transl Oncol. 2017 Feb;10(1):22-32.

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