PLK4

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. Overexpression of PLK4 results in centrosome amplification, and knockdown of PLK4 results in loss of centrosomes.

Structure

PLK4 contains an N-terminal kinase domain (residues 12-284) and a C-terminal localization domain (residues 596-898). 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.

As a cancer drug target

Inhibitors of the enzymatic activity PLK4 have potential in the treatment of cancer. 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.

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

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. Inhibition of PLK4 using a chemical genetic strategy has validated this p53-dependent cell cycle arrest in G1.

PLK4 was also identified as a potential therapeutic target for malignant rhabdoid tumors, medulloblastomas and possibly, other embryonal tumors of the brain.

Interactions and substrates

Documented PLK4 substrates include STIL, GCP6, Hand1, Ect2, FBXW5, and itself (via autophosphorylation). Autophosphorylation of PLK4 results in ubiquitination and subsequent destruction by the proteasome.

PLK4 has been shown to interact with Stratifin.

References

References

1. "Entrez Gene: PLK4 polo-like kinase 4 (Drosophila)".
2. (August 2014). "Structure of the C. elegans ZYG-1 cryptic polo box suggests a conserved mechanism for centriolar docking of Plk4 kinases". Structure.
3. (June 2014). "Oncogene-like induction of cellular invasion from centrosome amplification". Nature.
4. (November 2005). "The Polo kinase Plk4 functions in centriole duplication". Nature Cell Biology.
5. (November 2012). "The structure of the plk4 cryptic polo box reveals two tandem polo boxes required for centriole duplication". Structure.
6. (April 2019). "Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer". International Journal of Molecular Sciences.
7. "Inhibition of Polo-like kinase 4 as an anti-cancer strategy". Cancer Research.
8. (August 2010). "Small-molecule inducer of cancer cell polyploidy promotes apoptosis or senescence: Implications for therapy". Cell Cycle.
9. (2013-06-18). "Experimental drug shows promise in treating breast, ovarian cancer". [[Canadian Broadcasting Corporation]].
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11. (June 2015). "Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4". Science.
12. (July 2015). "p53 protects against genome instability following centriole duplication failure". The Journal of Cell Biology.
13. (November 2017). "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.
14. (December 2017). "Inhibition of polo-like kinase 4 (PLK4): a new therapeutic option for rhabdoid tumors and pediatric medulloblastoma". Oncotarget.
15. (November 2018). "Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB)". Bioengineering.
16. (April 2019). "Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer". International Journal of Molecular Sciences.
17. (January 2012). "GCP6 is a substrate of Plk4 and required for centriole duplication". Journal of Cell Science.
18. (October 2007). "Nucleolar release of Hand1 acts as a molecular switch to determine cell fate". Nature Cell Biology.
19. (March 2001). "Late mitotic failure in mice lacking Sak, a polo-like kinase". Current Biology.
20. (April 2010). "Plk4 is required for cytokinesis and maintenance of chromosomal stability". Proceedings of the National Academy of Sciences of the United States of America.
21. (July 2011). "The SCF-FBXW5 E3-ubiquitin ligase is regulated by PLK4 and targets HsSAS-6 to control centrosome duplication". Nature Cell Biology.
22. (November 2013). "Regulation of autophosphorylation controls PLK4 self-destruction and centriole number". Current Biology.
23. (July 2010). "Plk4 trans-autophosphorylation regulates centriole number by controlling betaTrCP-mediated degradation". Journal of Cell Science.
24. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature.