View source for PLK1

{{Infobox_gene}}
'''Serine/threonine-protein kinase PLK1''', also known as '''polo-like kinase 1''' (PLK-1) or '''serine/threonine-protein kinase 13''' (STPK13), is an [[enzyme]] that in humans is encoded by the ''PLK1'' ([[polo-like kinase]] 1) [[gene]].<ref name="pmid8127874">{{cite journal | vauthors = Holtrich U, Wolf G, Bräuninger A, Karn T, Böhme B, Rübsamen-Waigmann H, Strebhardt K | title = Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 5 | pages = 1736–40 | date = March 1994 | pmid = 8127874 | pmc = 43238 | doi = 10.1073/pnas.91.5.1736 }}</ref>

== Structure ==

PLK1 consists of 603 [[amino acid]]s and is 66kDa. In addition to the [[N-terminus]] [[kinase]] domain, there are two conserved polo-box regions of 30 amino acids at the [[C-terminus]]. Kinase activity is regulated at least in part, by the polo-boxes that are functionally important for both [[auto-inhibition]] and [[subcellular localization]].<ref name="pmid14592974">{{cite journal | vauthors = Cheng KY, Lowe ED, Sinclair J, Nigg EA, Johnson LN | title = The crystal structure of the human polo-like kinase-1 polo box domain and its phospho-peptide complex | journal = The EMBO Journal | volume = 22 | issue = 21 | pages = 5757–68 | date = November 2003 | pmid = 14592974 | pmc = 275415 | doi = 10.1093/emboj/cdg558 }}</ref>

== Localization ==

During interphase, PLK1 localizes to [[centrosome]]s. In early [[mitosis]], it associates with [[mitotic spindle]] poles. A recombinant GFP-PLK1 protein localizes to [[centromere]]/[[kinetochore]] region, suggesting a possible role for chromosome separation.<ref name="pmid18215321">{{cite journal | vauthors = Lee KS, Oh DY, Kang YH, Park JE | title = Self-regulated mechanism of Plk1 localization to kinetochores: lessons from the Plk1-PBIP1 interaction | journal = Cell Division | volume = 3 | issue =  | pages = 4 | date = January 2008 | pmid = 18215321 | pmc = 2263035 | doi = 10.1186/1747-1028-3-4 }}</ref>

== Cell cycle regulation ==

Plk1 is an early trigger for G2/M transition. Plk1 supports the functional maturation of the centrosome in late G2/early [[prophase]] and establishment of the bipolar spindle. Plk1 phosphorylates and activates cdc25C, a [[phosphatase]] that dephosphorylates and activates the cyclinB/[[cdc2]] complex. Plk phosphorylates and activates components of the [[anaphase-promoting complex]] (APC). The APC, which is activated by Fizzy-Cdc20 family proteins, is a cell cycle [[ubiquitin-protein ligase]] (E3) that degrades [[mitotic cyclin]]s, chromosomal proteins that maintain cohesion of [[sister chromatids]], and [[anaphase]] inhibitors. Abnormal spindle (Asp), a Polo kinase substrate, is a [[microtubule]]-associated protein essential for correct behavior of [[spindle pole]]s and M-phase microtubules. Plk1 localizes to the central region of the spindle in late mitosis and associates with [[kinesin]]-like protein CHO1/MKLP1. The homologous [[motor protein]] in [[Drosophila]] is the pavarotti gene product (PAR).<ref name="pmid16627997">{{cite journal | vauthors = van de Weerdt BC, Medema RH | title = Polo-like kinases: a team in control of the division | journal = Cell Cycle | volume = 5 | issue = 8 | pages = 853–64 | date = April 2006 | pmid = 16627997 | doi = 10.4161/cc.5.8.2692 }}</ref>

Studies have shown that the loss of PLK1 expression can induce [[pro-apoptotic]] pathways and inhibit growth. Based on yeast and murine studies of [[meiosis]], 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 and [[chromosome segregation]] during meiosis I.<ref name="pmid19386263">{{cite journal | vauthors = Soung NK, Park JE, Yu LR, Lee KH, Lee JM, Bang JK, Veenstra TD, Rhee K, Lee KS | title = Plk1-dependent and -independent roles of an ODF2 splice variant, hCenexin1, at the centrosome of somatic cells | journal = Developmental Cell | volume = 16 | issue = 4 | pages = 539–50 | date = April 2009 | pmid = 19386263 | pmc = 2741019 | doi = 10.1016/j.devcel.2009.02.004 }}</ref>

== Role in tumorigenesis ==

Plk1 is considered a [[proto-oncogene]], whose [[overexpression]] is often observed in [[tumor]] cells. [[Aneuploidy]] and [[tumorigenesis]] can also result from [[centrosome]] abnormality, particularly centrosome amplification defects. Centrosome duplication and maturation regulated by Plk1 occurs from late [[S phase]] to prophase. Abnormal centrosome amplification may lead to [[multipolar 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 driving [[cell 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 soft [[agar]] and more importantly, these cells can form tumors in [[Nude mouse|nude mice]] due to PLK1 overexpression.<ref name="pmid17208431">{{cite journal | vauthors = Malumbres M, Barbacid M | title = Cell cycle kinases in cancer | journal = Current Opinion in Genetics & Development | volume = 17 | issue = 1 | pages = 60–5 | date = February 2007 | pmid = 17208431 | doi = 10.1016/j.gde.2006.12.008 }}</ref>

PLK1 has also been linked to known pathways that are altered during the [[neoplastic transformation]]. [[Retinoblastoma]] [[Tumor suppressor gene|tumor suppressor]] (RB) pathway activation results in the repression of PLK1 promoter in a SWI/SNF [[chromatin 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 the [[Tumor suppressor protein p53|tumor suppressor p53]] related pathways. Evidence suggests that PLK1 can inhibit [[transactivation]] and pro-apoptotic functions of p53 function by physical interaction and [[phosphorylation]].<ref name="pmid12732729">{{cite journal | vauthors = Liu X, Erikson RL | title = Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 10 | pages = 5789–94 | date = May 2003 | pmid = 12732729 | pmc = 156279 | doi = 10.1073/pnas.1031523100 }}</ref>

== Clinical significance ==

PLK1 is being studied as a target for [[cancer]] drugs. Many [[Colon cancer|colon]] and [[lung cancer]]s are caused by K-RAS mutations. These cancers are dependent on PLK1.

When PLK1 expression was silenced with [[RNA interference]] in [[cell culture]], K-RAS cells were selectively killed, without harming normal cells.<ref>Downward J, Finding the weakness in cancer, N Engl J Med, 361:922, Aug. 27, 2009</ref><ref name="pmid19490893">{{cite journal | vauthors = Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF, Wong KK, Elledge SJ | title = A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene | journal = Cell | volume = 137 | issue = 5 | pages = 835–48 | date = May 2009 | pmid = 19490893 | pmc = 2768667 | doi = 10.1016/j.cell.2009.05.006 }}</ref>

PLK1 inhibitor [[volasertib]] is being evaluated in [[clinical trial]]s for use in [[acute myeloid leukemia]] (AML).<ref name="pmid27140825">{{cite journal | vauthors = Van den Bossche J, Lardon F, Deschoolmeester V, De Pauw I, Vermorken JB, Specenier P, Pauwels P, Peeters M, Wouters A | title = Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor | journal = Medicinal Research Reviews | volume = 36 | issue = 4 | pages = 749–86 | date = July 2016 | pmid = 27140825 | doi = 10.1002/med.21392 }}</ref> A combination of PLK1 and EGFR inhibition overcomes T790M-mediated drug resistance ''in vitro'' and ''in vivo'' in non-small cell lung cancer (NSCLC).<ref>{{cite journal | vauthors = Wang Y, Singh R, Wang L, Nilsson M, Goonatilake R, Tong P, Li L, Giri U, Villalobos P, Mino B, Rodriguez-Canales J, Wistuba I, Wang J, Heymach JV, Johnson FM | title = Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations | journal = Oncotarget | volume = 7 | issue = 30 | pages = 47998–48010 | date = July 2016 | pmid = 27384992 | pmc = 5216995 | doi = 10.18632/oncotarget.10332 }}</ref> In HNSCC mutations of the AJUBA mediate sensitivity to treatment with cell-cycle inhibitors including Plk1 inhibitor volasertib.<ref>{{cite journal | vauthors = Zhang M, Singh R, Peng S, Mazumdar T, Sambandam V, Shen L, Tong P, Li L, Kalu NN, Pickering CR, Frederick M, Myers JN, Wang J, Johnson FM | title = Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors | journal = Cancer Letters | volume = 392 | pages = 71–82 | date = April 2017 | pmid = 28126323 | pmc = 5404895 | doi = 10.1016/j.canlet.2017.01.024 }}</ref>

[[Rigosertib]] is an experimental RAS/PI3K/PLK1 inhibitor.<ref name=Nuthalapati2012>{{cite journal | vauthors = Nuthalapati S, Zhou Q, Guo P, Lv H, Cosenza S, Reddy MV, Reddy EP, Gallo JM | title = Preclinical pharmacokinetic and pharmacodynamic evaluation of novel anticancer agents, ON01910.Na (Rigosertib, Estybon™) and ON013105, for brain tumor chemotherapy | journal = Pharmaceutical Research | volume = 29 | issue = 9 | pages = 2499–511 | date = September 2012 | pmid = 22678771 | doi = 10.1007/s11095-012-0780-y }}</ref>

== Interactions ==

PLK1 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[CHEK2]],<ref name = "pmid12493754">{{cite journal | vauthors = Tsvetkov L, Xu X, Li J, Stern DF | title = Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody | journal = The Journal of Biological Chemistry | volume = 278 | issue = 10 | pages = 8468–75 | date = March 2003 | pmid = 12493754 | doi = 10.1074/jbc.M211202200 }}</ref> 
* [[NUDC]],<ref name = "pmid12852857">{{cite journal | vauthors = Zhou T, Aumais JP, Liu X, Yu-Lee LY, Erikson RL | title = A role for Plk1 phosphorylation of NudC in cytokinesis | journal = Developmental Cell | volume = 5 | issue = 1 | pages = 127–38 | date = July 2003 | pmid = 12852857 | doi = 10.1016/s1534-5807(03)00186-2 }}</ref> 
* [[PIN1]],<ref name = "pmid9499405">{{cite journal | vauthors = Shen M, Stukenberg PT, Kirschner MW, Lu KP | title = The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins | journal = Genes & Development | volume = 12 | issue = 5 | pages = 706–20 | date = March 1998 | pmid = 9499405 | pmc = 316589 | doi = 10.1101/gad.12.5.706 }}</ref><ref name = "pmid10037602">{{cite journal | vauthors = Lu PJ, Zhou XZ, Shen M, Lu KP | title = Function of WW domains as phosphoserine- or phosphothreonine-binding modules | journal = Science | volume = 283 | issue = 5406 | pages = 1325–8 | date = February 1999 | pmid = 10037602 | doi = 10.1126/science.283.5406.1325 }}</ref> 
* [[PSMA3]],<ref name = "pmid14647413">{{cite journal | vauthors = Lee M, Daniels MJ, Venkitaraman AR | title = Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression | journal = Oncogene | volume = 23 | issue = 4 | pages = 865–72 | date = January 2004 | pmid = 14647413 | doi = 10.1038/sj.onc.1207223 }}</ref><ref name = "pmid12815053">{{cite journal | vauthors = Lin HR, Ting NS, Qin J, Lee WH | title = M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex | journal = The Journal of Biological Chemistry | volume = 278 | issue = 38 | pages = 35979–87 | date = September 2003 | pmid = 12815053 | doi = 10.1074/jbc.M210659200 }}</ref> 
* [[PSMA5]],<ref name = pmid11205743/> 
* [[PSMA6]],<ref name = pmid11205743/> 
* [[PSMA7]],<ref name = "pmid11205743">{{cite journal | vauthors = Feng Y, Longo DL, Ferris DK | title = Polo-like kinase interacts with proteasomes and regulates their activity | journal = Cell Growth & Differentiation | volume = 12 | issue = 1 | pages = 29–37 | date = January 2001 | pmid = 11205743 | doi =  }}</ref> 
* [[PSMB3]],<ref name = pmid11205743/> and
* [[TSC1]].<ref name = "pmid16339216">{{cite journal | vauthors = Astrinidis A, Senapedis W, Henske EP | title = Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner | journal = Human Molecular Genetics | volume = 15 | issue = 2 | pages = 287–97 | date = January 2006 | pmid = 16339216 | doi = 10.1093/hmg/ddi444 }}</ref> 
{{Div col end}}

Structural analysis has been used to explain the broad specificity of PLK1.<ref name = "pmid20711360">{{cite journal | vauthors = Huggins DJ, McKenzie GJ, Robinson DD, Narváez AJ, Hardwick B, Roberts-Thomson M, Venkitaraman AR, Grant GH, Payne MC | title = Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation | journal = PLoS Computational Biology | volume = 6 | issue = 8 | date = August 2010 | pmid = 20711360 | pmc = 2920843 | doi = 10.1371/journal.pcbi.1000880 }}</ref>

== See also ==
* [[Polo-like kinase]]s, the gene family that PLK1 belongs to

== References ==
{{reflist|2}}

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