PLK4: A Master Regulator of Centriole Duplication and Cancer Susceptibility
Comprehensive genomic and functional analysis of PLK4, a serine/threonine-protein kinase essential for centriole biogenesis and implicated in microcephaly and tumorigenesis.
Gene Information Card
| Symbol | PLK4 |
|---|---|
| Full Name | polo like kinase 4 |
| Gene Type | protein-coding |
| Chromosomal Location | 4q28.1 |
| NCBI Gene ID | 10733 ncbi.nlm.nih.gov/gene/10733 |
| Ensembl ID | ENSG00000142731 |
| UniProt ID | O00444 |
| OMIM ID | 605031 |
| HGNC ID | 9077 |
| Aliases | SAK, STK18, MCPH7 |
Description
PLK4 encodes a serine/threonine-protein kinase that is a key regulator of centriole duplication. It is required for the formation of a single procentriole per mother centriole during the cell cycle. PLK4 activity is tightly controlled; overexpression leads to centriole amplification and genomic instability, while loss-of-function mutations cause centriole depletion and are associated with primary microcephaly. The gene is also implicated in various cancers, including breast, colorectal, and hepatocellular carcinoma.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Primary microcephaly 7 (MCPH7) | Loss-of-function mutations in PLK4 impair centriole duplication, leading to reduced neural progenitor cell proliferation and small brain size. | OMIM #605031; PMID: 24607474 |
| Breast cancer | PLK4 overexpression drives centrosome amplification, aneuploidy, and tumor progression. | COSMIC; PMID: 25605248 |
| Colorectal cancer | PLK4 upregulation correlates with poor prognosis and promotes chromosomal instability. | COSMIC; PMID: 29127259 |
| Hepatocellular carcinoma | PLK4 amplification and overexpression contribute to centrosome clustering and tumor growth. | COSMIC; PMID: 30093503 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 15.2 | Medium |
| Bone marrow | 10.5 | Medium |
| Lymph node | 8.3 | Low |
| Brain | 4.1 | Low |
| Liver | 3.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 12.1 | Cervical cancer cell line |
| MCF7 | 9.8 | Breast cancer cell line |
| HCT116 | 11.4 | Colorectal cancer cell line |
| HEK293 | 7.2 | Embryonic kidney cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.277C>T (p.Arg93*) | Nonsense | Rare | Loss of function; associated with microcephaly |
| c.1465G>A (p.Glu489Lys) | Missense | Rare | Impaired kinase activity; microcephaly |
| c.1912C>T (p.Arg638Trp) | Missense | Rare | Reduced centriole duplication; microcephaly |
| Amplification | Copy number gain | Frequent in cancer | Overexpression; centrosome amplification |
Mutation functional classification
Loss of Function (LOF)
Nonsense and missense mutations (e.g., p.Arg93*, p.Glu489Lys) that reduce or abolish kinase activity, leading to centriole duplication defects and microcephaly.
Gain of Function (GOF)
Gene amplification and overexpression in cancers, resulting in centrosome amplification and genomic instability.
Dominant Negative (DN)
Not well documented; some missense variants may exert dominant-negative effects by interfering with wild-type PLK4 function, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Centrosome duplication (Reactome: R-HSA-380270)
• Cell cycle (KEGG: hsa04110)
• PLK4 signaling events (PID: plk4_pathway)
Protein Summary
PLK4 is a 970-amino acid serine/threonine-protein kinase with an N-terminal kinase domain, a polo-box domain, and a C-terminal cryptic polo-box. It localizes to centrioles and is essential for procentriole formation. Autophosphorylation and degradation by the proteasome regulate its activity. In cancer, PLK4 overexpression promotes centrosome amplification, while in microcephaly, loss-of-function mutations impair neurogenesis.
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