PLK4

Polo-like kinase 4 (PLK4) is an enzyme that in humans is encoded by the PLK4 gene. PLK4 is a member of the polo family of serine/threonine protein kinases that play a critical role in cell cycle progression, mitosis, cytokinesis, and the maintenance of genomic stability. The activity and stability of PLK4 are tightly regulated through various post-translational modifications and protein-protein interactions, making it a key regulator of centriole duplication. Aberrant expression or mutation of PLK4 has been implicated in the development of various cancers, making it a potential target for cancer therapy.

Function

PLK4 is essential for the initiation of centriole duplication. It localizes to centrioles, where it phosphorylates substrates to initiate centriole biogenesis. The kinase activity of PLK4 is highest during the G1-S phase of the cell cycle, which is critical for the timing of centriole duplication. Overexpression of PLK4 can lead to the formation of supernumerary centrioles, which are a hallmark of cancer cells, whereas its depletion results in a failure of centriole duplication, leading to cell cycle arrest or cell death.

Regulation

The activity and stability of PLK4 are regulated by several mechanisms:

• Autophosphorylation: PLK4 undergoes autophosphorylation, which is essential for its kinase activity.
• Proteolytic degradation: The stability of PLK4 is controlled by the SCF (Skp, Cullin, F-box containing) complex, which targets it for ubiquitination and proteasomal degradation.
• Protein-protein interactions: PLK4 interacts with several proteins that regulate its activity and localization, including CEP152, CEP192, and STIL, which are involved in centriole biogenesis.

Clinical Significance

Alterations in PLK4 expression or activity have been associated with various cancers, including breast, pancreatic, and colorectal cancers. Overexpression of PLK4 can lead to genomic instability, a key feature of cancer cells, by promoting excessive centriole duplication. Conversely, reduced PLK4 activity can impair cell division, leading to genetic defects and cell death. Given its role in cell cycle regulation and centriole duplication, PLK4 is considered a potential target for cancer therapy. Inhibitors of PLK4 are currently being explored as therapeutic agents in cancer treatment.

Genetic Information

The PLK4 gene is located on chromosome 4q28 in humans. It consists of several exons and encodes a protein of approximately 970 amino acids. Mutations in the PLK4 gene have been linked to microcephaly and dwarfism, underscoring its importance in cell division and development.

See Also

• Cell cycle
• Centriole
• Mitosis
• Cytokinesis
• Genomic stability
• Cancer therapy