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Polo-like Kinases

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Polo-like Kinases Background

About Polo-like Kinases

Polo-like kinases (Plks) are regulatory serine/threonine kinases of the cell cycle involved in mitotic entry, mitotic exit, centrosome maturation, spindle formation, cytoplasmic division, and meiosis. Only one Plk is found in the genomes of Drosophila (Polo), budding yeast (Cdc5), and fission yeast (Plo1). However, vertebrates and other animals have many members of the Plk family, including Plk1, Plk2/Snk, Plk3/Prk/FnK, Plk4/Sak, and Plk5. These kinases are named for their homology to the Drosophila polo gene, which is essential for cell division in Drosophila.

Members of the polo-like kinase (PLK) family are important regulators of cell cycle progression, centromere replication, mitosis, cytoplasmic division, and the DNA damage response. PLKs undergo major changes in abundance, activity, localization, and structure at different stages of the cell cycle. They interact with other proteins in a tightly controlled spatial and temporal manner as part of a network that coordinates key cell cycle events.

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

Schematic diagram of the five Plk family genes in the human. Fig.1 Schematic diagram of the five Plk family genes in the human. (Lee SY, et al., 2014)

Mechanism of Action of Polo-like Kinases

Polo-like kinases (PLKs) exhibit complex mechanisms of regulation and activation, allowing them to fulfill their roles in cell cycle progression, mitosis, and other cellular processes. Here are the key mechanisms involved in the regulation of PLK activity:

  • Activation by Autophosphorylation and Transphosphorylation

PLKs undergo autophosphorylation events, where they phosphorylate themselves at specific sites within their kinase domains. Autophosphorylation is crucial for their activation and subsequent phosphorylation of downstream targets. Additionally, PLKs can also undergo transphosphorylation, where one PLK isoform phosphorylates and activates another isoform. This cross-activation mechanism contributes to the fine-tuning of PLK activities during cell cycle progression.

  • Protein-Protein Interactions

PLKs interact with a wide range of regulatory proteins, forming complexes that modulate their activity and subcellular localization. These interactions are mediated by specific protein domains present in PLKs and their binding partners. For example, PLKs interact with proteins involved in centrosome maturation, spindle assembly, and DNA damage response, enabling precise control over these cellular processes.

  • Cell Cycle-Dependent Expression and Localization

The expression levels and localization of PLKs are tightly regulated throughout the cell cycle. PLKs are typically low in abundance during the G1 and early S phases of the cell cycle but their levels increase as cells progress towards mitosis. In mitosis, PLKs localize to specific cellular structures such as the centrosomes, kinetochores, and the midbody, where they exert their functions. The precise localization of PLKs is mediated by their protein-protein interactions and regulated by phosphorylation events.

  • Phosphorylation of Downstream Targets

Once activated, PLKs phosphorylate a wide range of downstream targets involved in various cellular processes. PLK substrates include proteins associated with microtubule dynamics, centrosome maturation, kinetochore-microtubule attachments, and the mitotic checkpoint. By phosphorylating these substrates, PLKs regulate processes such as mitotic entry, spindle assembly, chromosome segregation, and cytokinesis.

  • Negative Regulation and Feedback Loops

The activity of PLKs is tightly controlled to ensure proper cell cycle progression and prevent aberrant signaling. Negative regulation of PLK activity involves the action of phosphatases, which dephosphorylate PLKs and their substrates, thereby reducing their activity. Additionally, feedback loops involving PLKs and other cell cycle regulators, such as cyclin-dependent kinases (CDKs), ensure proper coordination and timing of cell cycle events.

Functions of Polo-like Kinases

  • PLK1 is primarily involved in regulating mitosis and cell division.

Cell Cycle Regulation: PLK1 plays a crucial role in mitotic entry, spindle formation, chromosome segregation, and cytokinesis. It phosphorylates a wide range of substrates involved in microtubule dynamics, centrosome maturation, and mitotic checkpoint control.

Cancer Biology: PLK1 is frequently overexpressed in various cancers and is associated with tumor progression and poor prognosis. It has emerged as a potential target for cancer therapy.

  • PLK2 (SNK) and PLK3 (FNK/PRK) are involved in various cellular processes, including cell cycle regulation, DNA damage response, and neuronal functions.

Cell Cycle Regulation: PLK2 and PLK3 participate in cell cycle progression and mitotic processes, similar to PLK1. They regulate centrosome duplication, mitotic entry, and checkpoint control.

DNA Damage Response: PLK2 and PLK3 are activated in response to DNA damage and contribute to DNA repair pathways, cell cycle arrest, and apoptosis.

Neuronal Functions: PLK2 and PLK3 play roles in neuronal development, synaptic plasticity, and neurodegenerative diseases.

  • PLK4 (SAK) is essential for centriole duplication and maintaining genomic stability.

Centriole Duplication: PLK4 regulates centriole biogenesis and duplication, ensuring accurate formation of centrosomes and spindle poles during cell division.

Genomic Stability: Dysregulation of PLK4 can lead to centrosome amplification, chromosome missegregation, and genomic instability, which are associated with cancer development.

The mitotic roles of Polo-like kinase.Fig.2 The mitotic roles of Polo-Like kinase. (Donaldson MM, et al., 2011)

Available Resources for Polo-like Kinases

Polo-like kinases play critical roles in cell cycle regulation, mitosis, and various cellular processes. PLK1, PLK2, PLK3, and PLK4 are involved in different mechanisms and functions, affecting cell division, DNA damage response, and neuronal processes. Creative BioMart offers a wide selection of products to help researchers study the functions and mechanisms of Polo-like kinases in a variety of biological studies. The following Polo-like kinases are displayed, click to view all related molecules/targets and research reagents. For further information or to purchase products, please contact us. We are committed to providing the highest quality resources and support for your research to help you succeed.

References:

  1. Archambault V, Carmena M. Polo-like kinase-activating kinases: Aurora A, Aurora B, and what else? Cell Cycle. 2012 Apr 15;11(8):1490-5.
  2. Lee SY, Jang C, Lee KA. Polo-like kinases (plks), a key regulator of cell cycle and new potential target for cancer therapy. Dev Reprod. 2014;18(1):65-71.
  3. Donaldson MM, Tavares AA, Hagan IM, Nigg EA, Glover DM. The mitotic roles of Polo-like kinase. J Cell Sci. 2001;114(Pt 13):2357-2358.
  4. Barr F A, Silljé H H W, Nigg E A. Polo-like kinases and the orchestration of cell division[J]. Nature reviews Molecular cell biology, 2004, 5(6): 429-441.
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