PLKs

PLKs, or polo-like kinases, form a family of conserved serine/threonine kinases that regulate key aspects of cell division and other cellular processes. They share a catalytic N-terminal kinase domain and a C-terminal polo-box domain (PBD) that mediates substrate recognition and subcellular localization. Activation often involves phosphorylation, and substrate docking to the PBD enables precise timing and spatial control of phosphorylation events. For example, PLK1 is activated by autophosphorylation in its activation loop and then targets multiple mitotic substrates to coordinate progression through mitosis.

In humans, the PLK family includes PLK1, PLK2, PLK3, PLK4, PLK5 and PLK6. PLK1 is the best studied and is essential for entry into mitosis, centrosome maturation, spindle assembly, chromosome segregation and cytokinesis. PLK2 and PLK3 participate in stress responses and DNA damage signaling, with roles in neuronal function and hypoxic responses. PLK4 controls centriole duplication, with its misregulation linked to centrosome abnormalities and aneuploidy. PLK6 also contributes to cell cycle and centrosome functions, though its roles are less extensively characterized. PLK5 is generally considered catalytically inactive in humans and is often described as a non-kinase family member.

Regulation of PLKs involves phosphorylation, protein–protein interactions via the PBD, and control by upstream kinases and phosphatases. Localization to centrosomes, kinetochores, or the mitotic spindle is dynamically regulated during the cell cycle, enabling timing of substrate phosphorylation.

Clinical relevance centers on PLK1, which is frequently overexpressed in cancers and linked to poor prognosis. Small-molecule inhibitors targeting PLKs, notably PLK1, such as volasertib and onvansertib, are under clinical investigation, aiming to disrupt mitotic progression in cancer cells. Other PLK inhibitors and combination strategies are also explored, reflecting the therapeutic potential and challenges of targeting this kinase family.