PLK4

PLK4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2N19, 3COK, 4JXF, 4N7V, 4N7Z, 4N9J, 4YUR, 4YYP
Identifiers
Aliases	PLK4, SAK, STK18, MCCRP2, polo like kinase 4
External IDs	OMIM: 605031; MGI: 101783; HomoloGene: 7962; GeneCards: PLK4; OMA:PLK4 - orthologs
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q28.1 Start 127,880,893 bp[1] End 127,899,224 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 B Start 40,754,454 bp[2] End 40,771,318 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ventricular zone ganglionic eminence gonad sperm testicle left testis right testis bone marrow bone marrow cells rectum Top expressed in zygote tail of embryo secondary oocyte primary oocyte genital tubercle spermatid spermatocyte ventricular zone epiblast embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity kinase activity protein serine/threonine kinase activity protein binding ATP binding identical protein binding Cellular component cytoplasm centrosome deuterosome XY body nucleolus centriole cleavage furrow cytoskeleton nucleus cytosol Biological process trophoblast giant cell differentiation phosphorylation de novo centriole assembly involved in multi-ciliated epithelial cell differentiation G2/M transition of mitotic cell cycle centriole replication positive regulation of centriole replication ciliary basal body-plasma membrane docking regulation of G2/M transition of mitotic cell cycle protein phosphorylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10733 20873 Ensembl ENSG00000142731 ENSMUSG00000025758 UniProt O00444 Q64702 RefSeq (mRNA) NM_001190799 NM_001190801 NM_014264 NM_011495 NM_173169 RefSeq (protein) NP_001177728 NP_001177730 NP_055079 NP_035625 NP_775261 Location (UCSC) Chr 4: 127.88 – 127.9 Mb Chr 3: 40.75 – 40.77 Mb PubMed search [3] [4]
Wikidata
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Serine/threonine-protein kinase PLK4 also known as polo-like kinase 4 is an enzyme that in humans is encoded by the PLK4 gene.^[5] The Drosophila homolog is SAK, the C elegans homolog is zyg-1, and the Xenopus homolog is Plx4.^[6]

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.^[5] Overexpression of PLK4 results in centrosome amplification, and knockdown of PLK4 results in loss of centrosomes.^[7][8]

Structure

PLK4 contains an N-terminal kinase domain (residues 12-284) and a C-terminal localization domain (residues 596-898).^[9] 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.^[9]

As a cancer drug target

Inhibitors of the enzymatic activity PLK4 have potential in the treatment of cancer.^[10][11] 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.^[12]

Another PLK4 inhibitor, CFI-400945 has demonstrated efficacy in animal models of breast and ovarian cancer.^[13][14]

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.^[15] Inhibition of PLK4 using a chemical genetic strategy has validated this p53-dependent cell cycle arrest in G1.^[16]

PLK4 was also identified as a potential therapeutic target for malignant rhabdoid tumors, medulloblastomas and possibly, other embryonal tumors of the brain.^{[17][18][19][20]}

Interactions and substrates

Documented PLK4 substrates include STIL, GCP6,^[21] Hand1,^[22][23] Ect2,^[24] FBXW5,^[25] and itself (via autophosphorylation). Autophosphorylation of PLK4 results in ubiquitination and subsequent destruction by the proteasome.^[26][27]

PLK4 has been shown to interact with Stratifin.^[28]

References

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.