PLK1

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Polo-like kinase 1
Protein PLK1 PDB 1q4k.png
PDB rendering based on 1q4k.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PLK1 ; PLK; STPK13
External IDs OMIM602098 MGI97621 HomoloGene3690 ChEMBL: 3024 GeneCards: PLK1 Gene
EC number 2.7.11.21
RNA expression pattern
PBB GE PLK1 202240 at tn.png
PBB GE PLK1 gnf1h09404 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5347 18817
Ensembl ENSG00000166851 ENSMUSG00000030867
UniProt P53350 Q07832
RefSeq (mRNA) NM_005030 NM_011121
RefSeq (protein) NP_005021 NP_035251
Location (UCSC) Chr 16:
23.69 – 23.7 Mb
Chr 7:
122.16 – 122.17 Mb
PubMed search [1] [2]

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.[1]

Structure[edit]

PLK1 consists of 603 amino acids 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.[2]

Localization[edit]

During interphase, PLK1 localizes to centrosomes. 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.[3]

Cell cycle regulation[edit]

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 cyclins, 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 poles 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).[4]

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. [5]

Role in tumorigenesis[edit]

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 mice due to PLK1 overexpression.[6]

PLK1 has also been linked to known pathways that are altered during the neoplastic transformation. Retinoblastoma 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 p53 related pathways. Evidence suggests that PLK1 can inhibit transactivation and pro-apoptotic functions of p53 function by physical interaction and phosphorylation.[7]

Clinical significance[edit]

PLK1 is being studied as a target for cancer drugs. Many colon and lung cancers 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.[8][9]

Interactions[edit]

PLK1 has been shown to interact with PSMA7,[10] PSMA6,[10] NUDC,[11] PSMA5,[10] PSMA3,[12][13] TSC1,[14] PIN1,[15][16] PSMB3[10] and CHEK2.[17] Structural analysis has been used to explain the broad specificity of PLK1.[18]

See also[edit]

References[edit]

  1. ^ Holtrich U, Wolf G, Bräuninger A, Karn T, Böhme B, Rübsamen-Waigmann H, Strebhardt K (March 1994). "Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors". Proc. Natl. Acad. Sci. U.S.A. 91 (5): 1736–40. doi:10.1073/pnas.91.5.1736. PMC 43238. PMID 8127874. 
  2. ^ Cheng KY, Lowe ED, Sinclair J, Nigg EA, Johnson LN (November 2003). "The crystal structure of the human polo-like kinase-1 polo box domain and its phospho-peptide complex". EMBO J. 22 (21): 5757–68. doi:10.1093/emboj/cdg558. PMC 275415. PMID 14592974. 
  3. ^ Lee KS, Oh DY, Kang YH, Park JE (2008). "Self-regulated mechanism of Plk1 localization to kinetochores: lessons from the Plk1-PBIP1 interaction". Cell Div 3: 4. doi:10.1186/1747-1028-3-4. PMC 2263035. PMID 18215321. 
  4. ^ van de Weerdt BC, Medema RH (April 2006). "Polo-like kinases: a team in control of the division". Cell Cycle 5 (8): 853–64. doi:10.4161/cc.5.8.2692. PMID 16627997. 
  5. ^ Soung NK, Park JE, Yu LR, Lee KH, Lee JM, Bang JK, Veenstra TD, Rhee K, Lee KS (April 2009). "Plk1-dependent and -independent roles of an ODF2 splice variant, hCenexin1, at the centrosome of somatic cells". Dev. Cell 16 (4): 539–50. doi:10.1016/j.devcel.2009.02.004. PMC 2741019. PMID 19386263. 
  6. ^ Malumbres M, Barbacid M (February 2007). "Cell cycle kinases in cancer". Curr. Opin. Genet. Dev. 17 (1): 60–5. doi:10.1016/j.gde.2006.12.008. PMID 17208431. 
  7. ^ Liu X, Erikson RL (May 2003). "Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells". Proc. Natl. Acad. Sci. U.S.A. 100 (10): 5789–94. doi:10.1073/pnas.1031523100. PMC 156279. PMID 12732729. 
  8. ^ Downward J, Finding the weakness in cancer, N Engl J Med, 361:922, Aug. 27, 2009
  9. ^ Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF, Wong KK, Elledge SJ (May 2009). "A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene". Cell 137 (5): 835–48. doi:10.1016/j.cell.2009.05.006. PMC 2768667. PMID 19490893. 
  10. ^ a b c d Feng Y, Longo DL, Ferris DK (January 2001). "Polo-like kinase interacts with proteasomes and regulates their activity". Cell Growth Differ. 12 (1): 29–37. PMID 11205743. 
  11. ^ Zhou T, Aumais JP, Liu X, Yu-Lee LY, Erikson RL (July 2003). "A role for Plk1 phosphorylation of NudC in cytokinesis". Dev. Cell 5 (1): 127–38. doi:10.1016/S1534-5807(03)00186-2. PMID 12852857. 
  12. ^ 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. PMID 14647413. 
  13. ^ Lin HR, Ting NS, Qin J, Lee WH (September 2003). "M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex". J. Biol. Chem. 278 (38): 35979–87. doi:10.1074/jbc.M210659200. PMID 12815053. 
  14. ^ 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". Hum. Mol. Genet. 15 (2): 287–97. doi:10.1093/hmg/ddi444. PMID 16339216. 
  15. ^ Shen M, Stukenberg PT, Kirschner MW, Lu KP (March 1998). "The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins". Genes Dev. 12 (5): 706–20. doi:10.1101/gad.12.5.706. PMC 316589. PMID 9499405. 
  16. ^ Lu PJ, Zhou XZ, Shen M, Lu KP (February 1999). "Function of WW domains as phosphoserine- or phosphothreonine-binding modules". Science 283 (5406): 1325–8. doi:10.1126/science.283.5406.1325. PMID 10037602. 
  17. ^ Tsvetkov L, Xu X, Li J, Stern DF (March 2003). "Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody". J. Biol. Chem. 278 (10): 8468–75. doi:10.1074/jbc.M211202200. PMID 12493754. 
  18. ^ Huggins DJ, McKenzie GJ, Robinson DD, Narváez AJ, Hardwick B, Roberts-Thomson M, Venkitaraman AR, Grant GH, Payne MC (2010). "Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation". PLoS Comput. Biol. 6 (8). doi:10.1371/journal.pcbi.1000880. PMC 2920843. PMID 20711360.