Mitotic Roles of Polo-Like Kinase

The polo-like kinases (PLKs) make up an evolutionarily conserved, newly emerging family of essential cell cycle regulators. Polo kinases regulate diverse cellular and biochemical events at various stages of the M-phase. They are required at several key points through mitosis, starting from control of the G2/M transition through phosphorylation of CDC25C and mitotic cyclins and in the DNA damage checkpoint adaptation to prevent entry into mitosis. At the beginning of mitosis, various proteins are recruited to the centrosome, a maturation process which requires polo kinases. Polo kinases are also required for the establishment of a bipolar spindle. They have a role in the metaphase to anaphase transition via its interaction with the APC/cyclosome.At the onset of mitosis, eukaryotic cells undergo profound structural rearrangements that are regulated by protein phosphorylation. CDC2 has a basal phosphatase activity that partially activates CDC2 by removing the inhibitory phosphates added by Wee1 and Myt1. CDC25 is then further activated, which results in the burst of CDC2 activation needed for mitotic entry. PLK directly activate CDC25 and plays a role in the positive feedback loop that operates during CDC2 activation at the G2-M transition. Several protein kinases such as Chk2/Rad53 and PP2A inhibit PLK activation of CDC25. Growth factors like TGF-β also inhibit the phosphorylation of CDC25. PLKs have a role in centrosome maturation and separation. They facilitate recruitment of γ-tubulin and activate Asp (a microtubule-associated protein) at the centrosome. The chaperone HSP90 is pivotal for stability and function of PLK. HsEg5 is phosphorylated and activated by CDC2-cyclin-B, which in turn is activated by PLK. During M-Phase the PLKs activate certain functions of the APC/cyclosome, an E3 ubiquitin protein ligase that directs the proteasomal degradation of anaphase inhibitors. Both securin and CDC2's activating subunit cyclin-B are ubiquitinated at the onset of anaphase by the APC/cyclosome, leading to their proteasome dependent degradation and to separase activation. The substrate specificity of APC is regulated by its interactions with FZR1. APC/FZR1 complex directs the breakdown of components that inhibit sister chromatid separation, such as the securin Pds1. This leads to activation of the separin Esp1, which cleaves the cohesin Scc1. Cohesin consists of four subunits: two SMC proteins, Smc1 and Smc3, the so-called "kleisin" subunit Scc1, and Scc3. Cells of humans, xenopus, and other higher eukaryotes contain two mitotic orthologs of Scc3, called SA1 and SA2. PTTG1 which is a substrate of anaphase promoting complex (APC), is associated with Esp1 until activation of the APC. Protein regulator of cytokinesis-1(PRC1) is also required to maintain the spindle midzone and for the cleavage process.In addition to the described roles for PLKs during entry into and exit from mitosis, PLKs also promote the onset of cytokinesis. PLK1 interacts with MKLP1 during anaphase and telophase, which is required for the organization of the central spindle and formation of a contractile ring. The septum inducing network has a two part GAP and a GTP-binding protein, which signals septum formation through the kinase CDC7. In contrast to PLK1, both PLK2 and PLK3 function in interphase cells. PLK3 remains relatively constant during the cell cycle, and its kinase activity peaks during late S- and G2-phases. Furthermore, PLK3 phosphorylates CDC25C resulting in inhibition of the activity of this protein whereas phosphorylation of cyclin-B by PLK1 results in its translocation from the cytosol to the nucleus, thus activating CDC2 kinase. PLK2 and PLK3 also function in the dendrites and somata of post-mitotic neurons.