Serine/threonine-protein kinase PLK1, also known aspolo-like kinase 1 (PLK-1) orserine/threonine-protein kinase 13 (STPK13), is anenzyme that in humans is encoded by thePLK1 (polo-like kinase 1)gene.[5]
PLK1 consists of 603amino acids and is 66kDa. In addition to theN-terminuskinase domain, there are two conserved polo-box regions of 30 amino acids at theC-terminus. Kinase activity is regulated at least in part, by the polo-boxes that are functionally important for bothauto-inhibition andsubcellular localization.[6]
During interphase, PLK1 localizes tocentrosomes. In earlymitosis, it associates withmitotic spindle poles. A recombinant GFP-PLK1 protein localizes tocentromere/kinetochore region, suggesting a possible role for chromosome separation.[7]
Plk1 is an early trigger for G2/M transition. Plk1 supports the functional maturation of the centrosome in late G2/earlyprophase and establishment of the bipolar spindle. Plk1 phosphorylates and activates cdc25C, aphosphatase that dephosphorylates and activates the cyclinB/cdc2 complex. Plk phosphorylates and activates components of theanaphase-promoting complex (APC). The APC, which is activated by Fizzy-Cdc20 family proteins, is a cell cycleubiquitin-protein ligase (E3) that degradesmitotic cyclins, chromosomal proteins that maintain cohesion ofsister chromatids, andanaphase inhibitors. Abnormal spindle (Asp), a Polo kinase substrate, is amicrotubule-associated protein essential for correct behavior ofspindle poles and M-phase microtubules. Plk1 localizes to the central region of the spindle in late mitosis and associates withkinesin-like protein CHO1/MKLP1. The homologousmotor protein inDrosophila is the pavarotti gene product (PAR).[8] Studies have shown that the loss of PLK1 expression can inducepro-apoptotic pathways and inhibit growth.
Based on yeast and murine studies ofmeiosis, human PLK1 may also have a regulatory function in meiosis. S. cerevisiae polo kinase CDC5 is required to phosphorylate and remove meiotic cohesion during the first cell division. In CDC5 depleted cells, kinetochores are bioriented during meiosis I, and Mam1, a protein essential for coorientation, fails to associate with kinetochores. CDC5 is believed to have roles in sister-kinetochore coorientation andchromosome segregation during meiosis I.[9]
Plk1 is considered aproto-oncogene, whoseoverexpression is often observed intumor cells.Aneuploidy andtumorigenesis can also result fromcentrosome abnormality, particularly centrosome amplification defects. Centrosome duplication and maturation regulated by Plk1 occurs from lateS phase to prophase. Abnormal centrosome amplification may lead tomultipolar spindles and results in unequal segregation of chromosomes. Plk1 overexpression also increases the centrosome size and/or centrosome number, which will also lead to improper segregation of chromosomes, aneuploidy, and tumorigenesis.
Oncogenic properties of PLK1 are believed to be due to its role in drivingcell cycle progression. Supporting evidence comes from the overexpression studies of PLK1 in NIH3T3 cell line. These cells become capable of forming foci and growing in softagar and more importantly, these cells can form tumors innude mice due to PLK1 overexpression.[11]
PLK1 has also been linked to known pathways that are altered during theneoplastic transformation.Retinoblastomatumor suppressor (RB) pathway activation results in the repression of PLK1 promoter in a SWI/SNFchromatin remodeling complex dependent manner. In case of RB inactivation, PLK1 expression seems to be deregulated. This new finding suggests that PLK1 may be a target of the retinoblastoma tumor suppressor (RB) pathway.
Moreover, PLK1 seems to be involved in thetumor suppressor p53 related pathways. Evidence suggests that PLK1 can inhibittransactivation and pro-apoptotic functions of p53 function by physical interaction andphosphorylation.[12]
PLK1 is being studied as a target forcancer drugs. Manycolon andlung cancers are caused by K-RAS mutations. These cancers are dependent on PLK1.[citation needed]
When PLK1 expression was silenced withRNA interference incell culture, K-RAS cells were selectively killed, without harming normal cells.[13][14]
PLK1 inhibitorvolasertib is being evaluated inclinical trials for use inacute myeloid leukemia (AML).[15] A combination of PLK1 and EGFR inhibition overcomes T790M-mediated drug resistancein vitro andin vivo in non-small cell lung cancer (NSCLC).[16] In HNSCC mutations of the AJUBA mediate sensitivity to treatment with cell-cycle inhibitors including Plk1 inhibitor volasertib.[17] In mesenchymal NSCLC cells, cMet phosphorylation is regulated by Plk1‐mediated vimentin phosphorylation via β1‐integrin. The combination of cMet and Plk1 inhibition led to significant tumor regression in NSCLC in vivo models treated with clinically relevant drugs.[18]
Rigosertib is an experimental RAS/PI3K/PLK1 inhibitor.[19]
^Malumbres M, Barbacid M (February 2007). "Cell cycle kinases in cancer".Current Opinion in Genetics & Development.17 (1):60–5.doi:10.1016/j.gde.2006.12.008.PMID17208431.
^Van den Bossche J, Lardon F, Deschoolmeester V, De Pauw I, Vermorken JB, Specenier P, et al. (July 2016). "Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor".Medicinal Research Reviews.36 (4):749–86.doi:10.1002/med.21392.PMID27140825.S2CID3456912.
^Lee M, Daniels MJ, Venkitaraman AR (January 2004). "Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression".Oncogene.23 (4):865–72.doi:10.1038/sj.onc.1207223.PMID14647413.S2CID19552050.
^abcdFeng Y, Longo DL, Ferris DK (January 2001). "Polo-like kinase interacts with proteasomes and regulates their activity".Cell Growth & Differentiation.12 (1):29–37.PMID11205743.
^Astrinidis A, Senapedis W, Henske EP (January 2006). "Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner".Human Molecular Genetics.15 (2):287–97.doi:10.1093/hmg/ddi444.PMID16339216.
