Biology:PLK4

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Serine/threonine-protein kinase PLK4 also known as polo-like kinase 4 is an enzyme that in humans is encoded by the PLK4 gene.[1] The Drosophila homolog is SAK, the C elegans homolog is zyg-1, and the Xenopus homolog is Plx4.[2]

Function

PLK4 encodes a member of the polo family of serine/threonine protein kinases. The protein localizes to centrioles—complex microtubule-based structures found in centrosomes—and regulates centriole duplication during the cell cycle.[1] Overexpression of PLK4 results in centrosome amplification, and knockdown of PLK4 results in loss of centrosomes.[3][4]

Structure

PLK4 contains an N-terminal kinase domain (residues 12-284) and a C-terminal localization domain (residues 596-898).[5] Other polo-like kinase members contain 2 C-terminal polo box domains (PBD). PLK4 contains these 2 domains in addition to a third PBD, which facilitates oligomerization, targeting, and promotes trans-autophosphorylation, limiting centriole duplication to once per cell cycle.[5]

As a cancer drug target

Inhibitors of the enzymatic activity PLK4 have potential in the treatment of cancer.[6][7] The PLK4 inhibitor R1530 down regulates the expression of mitotic checkpoint kinase BubR1 that in turn leads to polyploidy rendering cancer cells unstable and more sensitive to cancer chemotherapy. Furthermore, normal cells are resistant to the polyploidy inducing effects of R1530.[8]

Another PLK4 inhibitor, CFI-400945 has demonstrated efficacy in animal models of breast and ovarian cancer.[9][10]

Another PLK4 inhibitor, centrinone, has been reported to deplete centrioles in human and other vertebrate cell types, which resulted in a p53-dependent cell cycle arrest in G1.[11] Inhibition of PLK4 using a chemical genetic strategy has validated this p53-dependent cell cycle arrest in G1.[12]

PLK4 was also identified as a potential therapeutic target for malignant rhabdoid tumors, medulloblastomas and possibly, other embryonal tumors of the brain.[13][14][15][16]

Interactions and substrates

Documented PLK4 substrates include STIL, GCP6,[17] Hand1,[18][19] Ect2,[20] FBXW5,[21] and itself (via autophosphorylation). Autophosphorylation of PLK4 results in ubiquitination and subsequent destruction by the proteasome.[22][23]

PLK4 has been shown to interact with Stratifin.[24]

References

  1. ↑ 1.0 1.1 "Entrez Gene: PLK4 polo-like kinase 4 (Drosophila)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10733. 
  2. ↑ "Structure of the C. elegans ZYG-1 cryptic polo box suggests a conserved mechanism for centriolar docking of Plk4 kinases". Structure 22 (8): 1090–1104. August 2014. doi:10.1016/j.str.2014.05.009. PMID 24980795. 
  3. ↑ "Oncogene-like induction of cellular invasion from centrosome amplification". Nature 510 (7503): 167–71. June 2014. doi:10.1038/nature13277. PMID 24739973. Bibcode: 2014Natur.510..167G. 
  4. ↑ "The Polo kinase Plk4 functions in centriole duplication". Nature Cell Biology 7 (11): 1140–6. November 2005. doi:10.1038/ncb1320. PMID 16244668. 
  5. ↑ 5.0 5.1 "The structure of the plk4 cryptic polo box reveals two tandem polo boxes required for centriole duplication". Structure 20 (11): 1905–17. November 2012. doi:10.1016/j.str.2012.08.025. PMID 23000383. 
  6. ↑ "Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer". International Journal of Molecular Sciences 20 (9): 2112. April 2019. doi:10.3390/ijms20092112. PMID 31035676. 
  7. ↑ "Inhibition of Polo-like kinase 4 as an anti-cancer strategy". Abstract LB-215. Cancer Research. pp. LB-215. http://cancerres.aacrjournals.org/cgi/content/meeting_abstract/71/8_MeetingAbstracts/LB-215. 
  8. ↑ "Small-molecule inducer of cancer cell polyploidy promotes apoptosis or senescence: Implications for therapy". Cell Cycle 9 (16): 3364–75. August 2010. doi:10.4161/cc.9.16.12732. PMID 20814247. 
  9. ↑ "Experimental drug shows promise in treating breast, ovarian cancer". News. Canadian Broadcasting Corporation. 2013-06-18. http://www.cbc.ca/news/canada/toronto/story/2013/06/18/toronto-cancer-drug.html. 
  10. ↑ "Discovery of orally active anticancer candidate CFI-400945 derived from biologically promising spirooxindoles: success and challenges". European Journal of Medicinal Chemistry 95: 35–40. May 2015. doi:10.1016/j.ejmech.2015.03.020. PMID 25791677. 
  11. ↑ "Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4". Science 348 (6239): 1155–60. June 2015. doi:10.1126/science.aaa5111. PMID 25931445. 
  12. ↑ "p53 protects against genome instability following centriole duplication failure". The Journal of Cell Biology 210 (1): 63–77. July 2015. doi:10.1083/jcb.201502089. PMID 26150389. 
  13. ↑ "A functional screening of the kinome identifies the Polo-like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain". Pediatric Blood & Cancer 64 (11): e26551. November 2017. doi:10.1002/pbc.26551. PMID 28398638. 
  14. ↑ "Inhibition of polo-like kinase 4 (PLK4): a new therapeutic option for rhabdoid tumors and pediatric medulloblastoma". Oncotarget 8 (67): 111190–111212. December 2017. doi:10.18632/oncotarget.22704. PMID 29340047. 
  15. ↑ "Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB)". Bioengineering 5 (4): 96. November 2018. doi:10.3390/bioengineering5040096. PMID 30400339. 
  16. ↑ "Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer". International Journal of Molecular Sciences 20 (9): 2112. April 2019. doi:10.3390/ijms20092112. PMID 31035676. 
  17. ↑ "GCP6 is a substrate of Plk4 and required for centriole duplication". Journal of Cell Science 125 (Pt 2): 486–96. January 2012. doi:10.1242/jcs.093930. PMID 22302995. 
  18. ↑ "Nucleolar release of Hand1 acts as a molecular switch to determine cell fate". Nature Cell Biology 9 (10): 1131–41. October 2007. doi:10.1038/ncb1633. PMID 17891141. 
  19. ↑ "Late mitotic failure in mice lacking Sak, a polo-like kinase". Current Biology 11 (6): 441–6. March 2001. doi:10.1016/s0960-9822(01)00117-8. PMID 11301255. 
  20. ↑ "Plk4 is required for cytokinesis and maintenance of chromosomal stability". Proceedings of the National Academy of Sciences of the United States of America 107 (15): 6888–93. April 2010. doi:10.1073/pnas.0910941107. PMID 20348415. Bibcode: 2010PNAS..107.6888R. 
  21. ↑ "The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication". Nature Cell Biology 13 (8): 1004–9. July 2011. doi:10.1038/ncb2282. PMID 21725316. 
  22. ↑ "Regulation of autophosphorylation controls PLK4 self-destruction and centriole number". Current Biology 23 (22): 2245–54. November 2013. doi:10.1016/j.cub.2013.09.037. PMID 24184099. 
  23. ↑ "Plk4 trans-autophosphorylation regulates centriole number by controlling betaTrCP-mediated degradation". Journal of Cell Science 123 (Pt 13): 2163–9. July 2010. doi:10.1242/jcs.068502. PMID 20516151. http://jcs.biologists.org/content/joces/123/13/2163.full.pdf. 
  24. ↑ "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. October 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 

Further reading

External links

  • Overview of all the structural information available in the PDB for UniProt: O00444 (Human Serine/threonine-protein kinase PLK4) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: Q64702 (Mouse Serine/threonine-protein kinase PLK4) at the PDBe-KB.




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