Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Polo-Like Kinase (PLK)

  • Nitin Sharma
  • Rajni Vaid
  • Kamal Dev
  • Anuradha Sourirajan
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101760

Synonyms

 CaCdc5 (PLK in Candida albicans);  Cdc5 (PLK in Saccharomyces cerevisiae);  Plk1/SmPlk1;  Plk4/SmSak (PLKs in Schistosoma mansoni);  PLK1;  PLK2/hSNK;  PLK3/PRK;  PLK4/SAK;  PLK5 (PLKs in Homo sapiens);  Plk1;  Plk2/SNK;  PLK3/FNK;  Plk4 and Plk5 (PLKs in Mus musculus);  plk1;  plk2;  plk3;  ZYG-1 (PLKs in Caenorhabditis elegans);  PLK1;  PLK2;  PLK4/SAK (PLKs in Strongylocentrotus purpuratus);  plk1;  plk2b;  plk3;  plk4 (PLKs in Danio rerio);  PLKA (PLK in Aspergillus nidulans);  plo1 (PLK in Schizosaccharomyces pombe);  Plx1;  Plx2;  Plx3 (PLK in Xenopus laevis);  TbPLK (PLK in Trypanosoma brucei).

Historical Background

Different protein kinases govern the progression of cell cycle by the phosphorylation of an array of their respective substrates. The key cell cycle kinases are polo-like kinase (PLK), cyclin-dependent kinase (CDK), and aurora kinases (AURK), which are evolutionarily conserved in eukaryotes from yeast to humans (Vaid et al. 2016). Polo-like kinases are serine/threonine kinases characterized by the presence of a unique non-catalytic polo-box domain (consisting of one or two polo boxes) towards their C-terminus. PLKs are multitaskers that regulate a range of processes including DNA replication, DNA damage and repair, maintenance of the genome fidelity, and proliferation and development through the well-coordinated action of signaling cascades during both mitosis and meiosis.

During 1980s, genetic screens in the fruit fly, Drosophila melanogaster, led to the discovery of the founding member of PLK family, polo, whose mutations caused abnormal spindle poles and impaired mitotic and meiotic cell division (Fenton and Glover 1993). Subsequently, polo homologues were also identified in other eukaryotic model systems, including budding yeast Saccharomyces cerevisiae (Cdc5), fission yeast Schizosaccharomyces pombe (plo1), pathogenic yeast Candida albicans (CaCdc5), the fungus Aspergillus nidulans (PlkA), and the worm Caenorhabditis elegans (plk1, plk2, plk3, ZYG-1) (Archambault and Glover 2009; Zitouni et al. 2014; Vaid et al. 2016). Among the vertebrates, PLKs of frog Xenopus laevis (Plx1, Plx2, Plx3), humans Homo sapiens (Plk1, Plk2/hSNK, Plk3/PRK, Plk4/SAK, Plk5), and fish Danio rerio (plk1, plk2b, plk3, plk4) show marked sequence homology. PLKs have also been identified in sea urchin Strongylocentrotus purpuratus (PLK1, PLK2, and PLK4/SAK) and in two parasites, Schistosoma mansoni (Plk1/ SmPlk1, Plk4/ SmSak) and Trypanosoma brucei (TbPLK) (Fig. 1). No homologs of PLKs are reported so far in plants and believed to have been lost during evolution (Archambault and Glover 2009; Zitouni et al. 2014; Vaid et al. 2016).
Polo-Like Kinase (PLK), Fig. 1

An overview of the types of PLKs and their functions in different eukaryotes. The PLK members present in each organism are indicated along with their functions, with emphasis on the unique functions of the respective PLK. In most organisms, PLKs have been found to regulate cell cycle progression, while in some cases, PLKs are involved in development, diseases, and other unique functions. (?) indicates the absence of PLKs or no reported functions of the respective PLK (Adapted from Vaid et al. 2016)

Domain Organization of PLKs

The domain architecture of all PLKs is similar and depicts conservation amongst the organisms like fruit fly, budding yeast, fission yeast, parasites, frogs, mice, and humans. PLKs primarily comprise of conserved catalytically active region called kinase domain (KD), present at the amino terminal and a distinct non-catalytic signature motif termed as polo-box domain (PBD) at the carboxy terminal. In all PLKs, the PBD encompasses two polo boxes (PB1, PB2) with tandem repeats of few amino acids (~70), except PLK4, which harbors a single cryptic polo box (Lee et al. 2005; Park et al. 2010). The PBD mediates the subcellular localization of polo kinases and allows them to interact exquisitely with an array of substrates, thereby coordinating different stages of the cell division. The KD and PBD allosterically regulate each other’s activity (Vaid et al. 2016). The entire PBD acts a single phosphoserine/phospho-threonine binding unit through the recognition of the conserved sequence motifs like Ser [p-ser/p-Thr]-[Pro-X], showcasing the priming activity by other mitotic kinases (Lowery et al. 2005). There are two proposed models for PBD-mediated targeting of PLKs to the substrates. The processive model, in which the PLKs act temporally integrating the mitotic signaling cascade allowing the interaction between the PBD and substrate protein for its further phosphorylation by PLK. Distributive models showcase the spatial regulation by PBD through localization on a targeted single protein at specific sites, further allowing the kinase domain to phosphorylate different substrates at specific locales, thereby enabling the mitotic signaling to ensue (Lowery et al. 2005).

The members of PLK family share a high degree of structural as well as functional homology, e.g., the kinase domain of Cdc5, Plo1, and human PLK1 exhibit 49% identity, while PBDs of human PLK1 show 33–40% and 46–47% of identity with PBDs of Cdc5 and Plo1, respectively (Lee et al. 2005, Fig. 2). Accordingly, defects in cdc5 mutants of yeast can be complemented by human PLK1 and PLK3. Human PLK1 shows more functional relevance to budding yeast CDC5, indicating that cell cycle functions of PLKs are conserved across evolution from yeast to humans (Lee and Erikson 1997, Fig. 2).
Polo-Like Kinase (PLK), Fig. 2

Schematic representation of domain organization of PLKs and comparison of PLKs from S. cerevisiae (Cdc5), S. pombe (Plo1), and H. sapiens (Plk1). Both sequence identities and similarities (percentages in parenthesis) and position of amino acid residues are indicated. The KD of the two PLKs, Cdc5 and Plo1, show 49% identity and 69–70% similarity with KD of human Plk1; the two polo boxes including PB1 and PB2 of Cdc5 show 33% and 40% identity (57% and 53% similarity), respectively, with PB1 and PB2 of human PLK1, and 37% and 46% identity (54% and 61% similarity), respectively, in the case of PB1 and PB2 of Plo1

PLKs and Cell Cycle

Eukaryotic cell cycle is broadly divided into four phases, namely, the G1, S, G2, and M phases (Vaid et al. 2016). Many of the cell division cycle genes were first identified by studying yeast models, especially Saccharomyces cerevisiae (Nasmyth 1996). Genes involved in cell division cycle in yeast mutants are named as cdc (for “cell division cycle”) followed by an identifying number, e.g., Cdc25 or Cdc20. The correct passage of each stage of cell cycle needs coordination amongst numerous proteins. The major kinases involved in governing cell cycle are CDKs, Aurora kinases, and (PLKs). These serine threonine family of kinases phosphorylate their cell cycle substrates to drive cell cycle to different stages.

The functions of PLKs during cell cycle range from centrosome maturation in late G2 phase to the regulation of cytokinesis. PLKs have been implicated in various essential cell-cycle-related processes including centrosome maturation, Golgi dynamics, DNA damage response, mitotic entry, checkpoint recovery, spindle assembly, sister chromatid separation, and cytokinesis (Okhura et al. 1995; Lane and Nigg 1996, Fig. 3). PLKs do not play any role in the G1/S phase, except human PLK3, whose activity peaks in S-phase to phosphorylate Cdc25A and regulation of the cyclin E expression (Archambault and Glover 2009; Zitouni et al. 2014). The central role of the PLKs as molecular switches that coordinate the timing of entry into M phase in response to cellular signals seems to be an ancient function of these protein kinases. A comparison of the many cell division functions of PLKs in different organisms reveals that they participate in crucial and conserved cellular roles.
Polo-Like Kinase (PLK), Fig. 3

Mitotic functions of polo-like kinases. Picture showing the general functions of polo-like kinases in different phases of mitotic cell division. Bent arrows indicate the entry from one phase to other phase of cell cycle

Deletion of gene encoding PLK is lethal in all eukaryotic organisms studied, hence, proving that PLKs are essential for survival of the organism (Lowery et al. 2005). Overexpression of PLK isoforms in humans is also found to be linked with cancer biology. These kinases, when deregulated, have been strongly implicated in tumor initiation and development (Archambault et al. 2015).

PLKs in Mitosis and Meiosis

PLKs are committed to cell division and guard the events of mitosis (Qian et al. 2001). PLKs are essential for the G2/M progression. The G2/M transition is regulated by the activation of Cdk-cyclin B known as M-phase-promoting factor (MPF). In fission yeast, entry into mitosis is mediated through Cdk1-dependent pathway, whereas in budding yeast, Cdc5 inactivates the Swe1 inhibitor and activates CDK (Cdc28/Clb2), thus driving the entry into M phase. PLKs stimulate the mitotic spindle assembly and centrosome nucleation, which initiates in the G1/S phase and completed in the G2 phase.

The role of PLKs is indispensable and dynamic in action for the mitotic progression. PLKs including polo (fruit fly), Plo1 (fission yeast), and PLK1 (human) are required for the establishment of bipolar spindle assembly during metaphase except Cdc5 (budding yeast). PLK1 phosphorylates several kinetochore proteins (BubR1, Clip70, PBIP1), whereas both Cdc5 and Cdc7 in budding yeast catalyze the spindle formation. During metaphase to anaphase transition, PLKs mediate the phosphorylation of the cohesin subunit, SCC1 to facilitate their removal from chromosomal arms for separation of sister chromatids (Ohta et al. 2012; Vaid et al. 2016). During onset of anaphase, PLKs activate the anaphase-promoting complex (APC/cyclosome), which inactivates the anaphase inhibitors like securin in mammals and Pds1 in yeast. This leads to the activation of endopeptidase separase/separin (Cut1 in fission yeast, Esp1 in budding yeast, and separase in mammals) that catalyze the cleavage and subsequent removal of the cohesins Scc1 from chromosomal arms of sister chromatids (Ohta et al. 2012; Vaid et al. 2016). PLK-mediated activation of the APC promotes mitotic exit, leading to the downregulation of CDK and degradation of mitotic cyclins. PLKs are crucial for cytokinesis, which is a conserved process amongst all eukaryotes. PLKs trigger mitotic exit and cytokinesis by activating the major signaling pathways mitotic exit network (MEN) and Cdc Fourteen Early Anaphase Release (FEAR) in budding yeast, whereas septation initiation network (SIN) in fission yeast coordinate mitotic exit and cytokinesis. No such pathways are known for human PLK1 (Lee et al. 2005; Vaid et al. 2016).

Meiosis is an essential developmental pathway that maintains genetic diversity. PLKs regulate various meiotic events in different eukaryotic lineages. Meiotic chromosome pairing, synapsis, recombination, and pachytene exit are unique events of prolonged meiotic prophase I (Vaid et al. 2016). In Caenorhabditis elegans, pairing centers (PC) direct recruitment of PLK2 onto the chromosomes, which in turn promotes remodeling of nuclear envelope (NE), synapsis, and paring of the homologous chromosomes (Vaid et al. 2016).

PLKs, in different organisms, play a decisive role in the accomplishment of the pachytene stage and pachytene exit for meiotic progression during prophase I. Events of pachytene stage and pachytene exit have been well characterized in budding yeast. In budding yeast, the PLK, Cdc5, promotes synaptonemal complex (SC) disassembly and resolution of interhomolog connections/joint molecules into crossovers and chiasmata, thereby triggering pachytene exit (Lee and Amon 2003; Sourirajan and Lichten 2008). Mammalian PLK1 in mouse spermatocytes recruits to SC and phosphorylates the SC proteins, SYCP1 and TEX12, which leads to SC disassembly, thus, triggering meiotic prophase I exit (Vaid et al. 2016). In D. melanogaster, polo regulates oocyte determination through phosphorylation of Maelstrom protein that inactivates pachytene checkpoint in oocyte (Zitouni et al. 2014). In fission yeast, Plo1 is removed from spindle pole bodies (SPBs; centrosome equivalent in yeast) during meiotic prophase I to promote horse-tail nuclear movement for interhomolog recombination (Ohta et al. 2012). The excluded Plo1 is recruited to kinetochores in meiotic prophase I to mediate as yet unrevealed functions (Vaid et al. 2016).

PLKs regulate multiple events during meiotic divisions like regulation of cohesion, mono-orientation of sister kinetochores of the homologous chromosomes by promoting monopolin recruitment, spindle assembly, and meiotic exit (Lee and Amon 2003). PLKs ensure the accurate segregation of homologs in higher organisms and regulate microtubule organisation and cytokinesis in meiosis (Zitouni et al. 2014; Vaid et al. 2016).

PLKs and Cancer

PLKs are considered as the prognostic marker for cancer. As a crucial regulator of cell cycle, PLKs maintain integrity of eukaryotic genome. Extensive research conducted over the past decade revealed that PLK1 and other members of the kinase family are overexpressed in various types of cancer (Park et al. 2015). In humans, PLK1 is overexpressed in a wide range of cancer including breast cancer, ovarian cancer, endometrial cancer, colorectal cancer, gliomas, non-small cell lung cancer, thyroid cancer, head and neck cancer, esophageal cancer, gastric cancer, pancreatic cancer, and melanomas (He et al. 2009). Thus, PLKs have been targeted for anticancer therapy. The other kinases like Bora kinases are also involved in the regulation of PLK1 activity in cancer therapeutics (Cirillo et al. 2016). Given their importance in cell division, and their deregulation in malignant tissues, much effort has been made to discover and develop small chemical compounds that can inhibit or modulate PLK activity. Basically, two strategies are widely used to develop the PLK1 inhibitors viz. ATP-competitive analogues and PBD-binding antagonists (Park et al. 2015). Recently, several potent peptides were evaluated against full-length Plk1 (including KD and PBD), wherein PLHSpT was taken as control peptide, which is the current standard peptide used for inhibiting the PBD of Plk1 (Jang et al. 2016).

Summary

PLKs are members of serine/threonine kinases that are master regulators of the eukaryotic cell cycle. PLKs are unique due to the presence of the PBDs, which provide the intricate spatiotemporal regulation of phosphorylation of the protein substrates required in cell signaling. The primary functions of PLKs in cell division are conserved in different organisms. They govern the cell cycle progression, centriole duplication, chromosome dynamics, mitotic exit and cytokinesis, and the DNA damage/repair. During meiosis, PLKs regulate prophase I events like crossing over, pachytene exit, sister kinetochore mono-orientation, removal of cohesins, meiosis I and meiosis II transitions, and cytokinesis.

Depletion of the PLK gene has proved to be lethal in most eukaryotic organisms, hence, indicating that PLKs are essential for survival of the organism. The perturbations of PLK1 expression is correlated with cancer and tumorigenesis. Thus, PLKs act as potent candidates for drug designing and the development of specific inhibitors for targeting the specific substrates/stages of tumorigenesis. The conserved structural and functional homology of PLKs provide an insight for exploring fields of cancer biology, cellular signaling pathways, apoptosis, as well as their biochemistry and regulation. The substrate repertoire of PLKs and their kinome is yet another area for ongoing and future explorations.

References

  1. Archambault V, Glover DM. Polo-like kinases: conservation and divergence in their functions and regulation. Nat Rev Mol Cell Biol. 2009;10:265–75.PubMedCrossRefGoogle Scholar
  2. Archambault V, Lepine G, Kachaner D. Understanding the Polo kinase machine. Oncogene. 2015;34:4799–7.PubMedCrossRefGoogle Scholar
  3. Cirillo L, Thomas Y, Pintard L, Gotta M. BORA-dependent PLK1 regulation: A new weapon for cancer therapy? Mol Cell Oncol. 2016;3:e1199265.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Fenton B, Glover DM. A conserved mitotic kinase active at late anaphase-telophase in syncytial Drosophila embryos. Nature. 1993;363:637–40.PubMedCrossRefGoogle Scholar
  5. He ZL, Zheng H, Lin H, Miao XY, Zhong DW. Overexpression of polo-like kinase1 predicts a poor prognosis in hepatocellular carcinoma patients. World J Gastroenterol. 2009;15:4177–82.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Jang J, Terrence R, Burke JTR, Hymel D. Peptidomimetics targeting the Polo-box domain of Polo-like kinase 1. J Emerg Invest. 2016;8:1–7.Google Scholar
  7. Lane HA, Nigg EA. Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J Cell Biol. 1996;135:1701–13.PubMedCrossRefGoogle Scholar
  8. Lee BH, Amon A. Polo kinase-meiotic cell cycle coordinator. Cell Cycle. 2003;2:400–2.PubMedCrossRefGoogle Scholar
  9. Lee K, Erikson RL. Plk Is a functional homolog of Saccharomyces cerevisiae Cdc5, and elevated Plk activity induces multiple septation structures. Mol Cell Biol. 1997;17:3408–17.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Lee KS, Park JE, Asano S, Park CJ. Yeast polo-like kinases: functionally conserved multitask mitotic regulators. Oncogene. 2005;24:217–29.PubMedCrossRefGoogle Scholar
  11. Lowery DM, Lim D, Yaffe MB. Structure and function of Polo-like kinases. Oncogene. 2005;24:248–59.PubMedCrossRefGoogle Scholar
  12. Nasmyth K. At the heart of the budding yeast cell cycle. Trends Genet. 1996;12:405–12.Google Scholar
  13. Ohkura H, Hagan IM, Glover DM. The conserved Schizosaccharomyces pombe kinase plo1, required to form a bipolar spindle, the actin ring and septum can drive septum formation in G1 and G2 cells. Genes Dev. 1995;9:1059–73.PubMedCrossRefGoogle Scholar
  14. Ohta M, Sato M, Yamamoto M. Spindle pole body components are reorganized during fission yeast meiosis. Mol Biol Cell. 2012;23:1799–11.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Park JE, Soung NK, Johmura Y, Kang YH, Liao C, Lac KH, Park CH, Nicklaus MC, Lee KS. Polo box domain: a versatile mediator of polo-like kinase functions. Cell Mol Life Sci. 2010;67:1957–70.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Park JE, Kim TS, Meng L, Bang JK, Kim BY, Lee KS. Putting a bit into the polo-box domain of polo-like kinase 1. J Anal Sci Tech. 2015;6:27.CrossRefGoogle Scholar
  17. Qian YW, Erikson E, Taieb FE, Maller JL. The polo-like kinase Plx1 is required for activation of the phosphatase Cdc25C and cyclin B-Cdc2 in Xenopus oocytes. Mol Cell Biol. 2001;12:1791–9.CrossRefGoogle Scholar
  18. Sourirajan A, Lichten M. Polo-like kinase Cdc5 drives exit from pachytene during budding yeast meiosis. Genes Dev. 2008;22:2627–32.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Vaid R, Sharma N, Chauhan S, Deshta A, Dev K, Sourirajan A. Functions of polo-like kinases: a journey from yeast to humans. Protein Pept Lett. 2016;23:185–97.PubMedCrossRefGoogle Scholar
  20. Zitouni S, Nabais C, Jana SC, Guerrero A, Bettencourt-Dias M. Polo-like kinases: structural variations lead to multiple functions. Nat Rev Mol Cell Biol. 2014;15:433–52.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Nitin Sharma
    • 1
  • Rajni Vaid
    • 1
  • Kamal Dev
    • 1
  • Anuradha Sourirajan
    • 1
  1. 1.Faculty of Applied Sciences and BiotechnologyShoolini UniversitySolanIndia