Polo-like kinase

Polo-like kinases (Plks) are regulatory serine/threonin kinases of the cell cycle involved in mitotic entry, mitotic exit, spindle formation, cytokinesis, and meiosis. Only one Plk is found in the genomes of fruit flies (Polo), budding yeast (Cdc5) and fission yeast (Plo1). Vertebrates, however, have many Plk family members including Plk1 (Xenopus Plx1), Plk2/Snk (Xenopus Plx2), Plk3/Prk/FnK (Xenopus Plx3), Plk4/Sak and Plk5. Of the vertebrate Plk family members, the mammalian Plk1 has been most extensively studied. During mitosis and cytokinesis, Plks associate with several structures including the centrosome, kinetochores, and the central spindle.

The catalytic serine/threonine kinase domain of Plk is at the N-terminus of the protein. A regulatory domain containing two signature motifs, known as polo boxes, is located at the C-terminus. The polo-box domain (PBD) helps with specificity of substrate and localizes Plk to specific mitotic structures during mitosis. These include the centrosomes in early M phase, the spindle midzone in early and late anaphase and the midbody during cytokinesis.

Plks are controlled at the level of protein synthesis and stability, by the action of upstream kinases and phosphatases, and by localization to specific subcellular structures. Plks are activated by phosphorylation within a short region of the catalytic domain called the T-loop (or activation-loop), with several serine/threonine phosphorylation sites in the loop identified. Polo-like kinase kinase 1 (Plkk1) and protein kinase A (PKA) have been shown to be able to phosphorylate Plk1 in vitro. The polo-box domain (PBD) of Plk1 is a phosphopeptide-binding motif. In the absence of a phosphorylated ligand, the PBD interacts with the catalytic domain thereby preventing substrate binding or kinase activation. Occupancy of the PBD by an exogenous phosphopeptide ligand would then cause the release of the catalytic domain, which, together with phosphorylation on the T-loop, converts Plk to the active form. On exit from mitosis, Plks are proteolytically degraded through the ubiquitin-proteasome pathway after coming in contact with the ubiquitin-ligase Anaphase Promoting Complex (APC).

Plks have been found to cooperate with Cdks in the orchestration of cell division. Entry into M phase is controlled through the activation of cyclin-dependent kinase 1 (CDK1)–cyclin B, and Cdc25 is a phosphatase that dephosphorylates Cdk1 to promote mitotic entry. Plk1 binds to phosphorylated Cdc25 through its PBD. Thus Plks can phosphorylate Cdc25 and thereby regulate Cdc25 and indirectly Cdk1. A study shows that phosphorylation of a serine residue (Ser198) within a nuclear-export signal of Cdc25 promotes the nuclear accumulation of Ccdc25 in humans. PBD has high affinity for proteins already phosphorylated at certain serine/threonine sites. This requires priming of substrates by Plk itself or other kinases such as Cdk1 to create a docking site. However, there could also be phosphorylation-independent structural aspects contributing to binding. Plo1 (the Plk found in fission yeast) is part of a positive-feedback loop that controls the expression of genes that are required for cell division.

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