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POLO-LIKE KINASE 1; PLK1

POLO-LIKE KINASE 1; PLK1

Alternative titles; symbolsPOLO-LIKE KINASE; PLKSERINE/THREONINE PROTEIN KINASE 13; STPK13HGNC Approved Gene Symbol: PLK1Cytogenetic location: 16p12.2 Genomi...

Alternative titles; symbols

  • POLO-LIKE KINASE; PLK
  • SERINE/THREONINE PROTEIN KINASE 13; STPK13

HGNC Approved Gene Symbol: PLK1

Cytogenetic location: 16p12.2 Genomic coordinates (GRCh38): 16:23,678,888-23,690,366 (from NCBI)

▼ Cloning and Expression
The product of the Drosophila polo gene is a serine/threonine protein kinase which is involved in mitosis. Drosophila polo is related to the yeast CDC5 gene. The human homolog of the polo gene was cloned independently by Lake and Jelinek (1993), Holtrich et al. (1994), and Hamanaka et al. (1994). All reported that the human polo-like kinase (PLK) gene encodes a 603-amino acid polypeptide. Several nucleotide sequence differences were noted among the published sequences, but Hamanaka et al. (1994) stated that these differences encode conservative changes in the amino acid sequence and are likely to be polymorphisms. Hamanaka et al. (1994) reported that the molecular weight of the PLK protein is 66 kD. By Northern blot analysis, they showed PLK was not expressed in any adult human tissues except placenta. Among mouse tissues, expression was observed in adult thymus tissue and ovaries and in fetuses. Among cultured cell lines, the PLK message was detected in all growing cell lines. Hamanaka et al. (1994) noted that the level of PLK message was not induced by serum stimulation. Lake and Jelinek (1993) examined the level of PLK mRNA during the cell cycle of synchronized NIH 3T3 cells and found that the mRNA is absent or expressed at very low levels during the G1 phase, begins to reaccumulate during the S phase, and reaches maximal levels during the G2/M phase. Holtrich et al. (1994) observed that PLK transcripts are present at high levels in tumors of various origins.

▼ Gene Function
Golsteyn et al. (1995) expressed recombinant human PLK1 in insect cells and found that it phosphorylated casein (see 115450) on serine and threonine residues. PLK1 also phosphorylated myelin basic protein (MBP; 159430) and microtubule-associated protein-2 (MAP2; 157130), but to a lesser extent than casein. In synchronized HeLa cells, PLK1 activity was low during interphase and high during mitosis. Confocal microscopy showed that PLK1 bound components of the mitotic spindle at all stages of mitosis, but it was redistributed as cells progressed from metaphase to anaphase. Specifically, PLK1 associated with spindle poles up to metaphase, but it relocalized to the equatorial plane, where spindle microtubules overlapped, as cells went through anaphase. Golsteyn et al. (1995) concluded that PLK1 functions in mitotic cells to control spindle dynamics and chromosome segregation.

Smith et al. (1997) showed that microinjection of PLK mRNA induced mitosis in quiescent NIH 3T3 cells. Constitutive expression of PLK caused NIH 3T3 cells to proliferate in low serum media, but at a lower rate than cells transformed with v-Ras (179555) or v-Src (190090). Cells transformed with PLK grew in soft agar and produced tumors in nude mice. Smith et al. (1997) concluded that PLK may be involved in the promotion or progression of cancers.

In vertebrate cells, nuclear entry of mitosis-promoting factor (MPF; see cyclin B1, 123836) during prophase is thought to be essential for induction and coordination of M-phase events. Phosphorylation of cyclin B1 is central to its nuclear translocation. Toyoshima-Morimoto et al. (2001) purified a protein kinase from Xenopus M-phase extracts that phosphorylated a crucial serine (S147) in the middle of the nuclear export signal of cyclin B1. They identified this kinase as Plx1, a Xenopus homolog of PLK1. During cell cycle progression in HeLa cells, a change in the kinase activity of endogenous PLK1 toward S147 and/or S133 correlated with kinase activity in the cell extracts. An anti-PLK1 antibody depleted the M-phase extracts of the kinase activity toward S147 and/or S133. An anti-phospho-S147 antibody reacted specifically with cyclin B1 only during G2/M phase. A mutant cyclin B1 in which S133 and S147 were replaced by alanines remained in the cytoplasm, whereas wildtype cyclin B1 accumulated in the nucleus during prophase. Coexpression of constitutively active PLK1 stimulated nuclear entry of cyclin B1. Toyoshima-Morimoto et al. (2001) concluded that PLK1 may be involved in targeting MPF to the nucleus during prophase.

Elia et al. (2003) used a proteomic screen to identify the polo-box domain of PLK1 as a specific phosphoserine or phosphothreonine binding domain and determined its optimal binding motif. This motif is present in PLK1 substrates such as CDC25 (157680), and an optimal phosphopeptide containing the motif disrupted polo-box domain-substrate binding and localization of the polo-box domain to centrosomes. Elia et al. (2003) concluded that their observations revealed how PLK1 can localize to specific sites within cells in response to CDK phosphorylation at those sites and provided a structural mechanism for targeting the PLK1 kinase domain to its substrates.

Meiosis is a specialized cell division in which 2 chromosome segregation phases follow a single DNA replication phase. Lee and Amon (2003) studied the S. cerevisiae Polo-like kinase CDC5, whose human homolog is PLK, and found it to be instrumental in establishing the meiosis I chromosome segregation program. CDC5 was required to phosphorylate and remove meiotic cohesin from chromosomes. Furthermore, in the absence of CDC5, kinetochores were bioriented during meiosis I, and Mam1, a yeast protein essential for coorientation, failed to associate with kinetochores. Thus, sister-kinetochore coorientation and chromosome segregation during meiosis I are coupled through their dependence upon CDC5.

Elevated expression of PLK1 occurs in many different types of cancer, and PLK1 has been proposed as a diagnostic marker for several tumors. Liu and Erikson (2003) used the vector-based small interfering RNA (siRNA) technique to specifically deplete PLK1 in cancer cells. They found that such depletion dramatically inhibited cell proliferation, decreased viability, and resulted in cell-cycle arrest with a 4 N DNA content. The formation of dumbbell-like chromatin structure suggested the inability of these cells to completely separate the sister chromatids at the onset of anaphase. PLK1 depletion induced apoptosis, as indicated by the appearance of subgenomic DNA in fluorescence-activated cell-sorter (FACS) profiles, the activation of caspase-3 (600636), and the formation of fragmented nuclei. The p53 pathway (191170) was shown to be involved in PLK1 depletion-induced apoptosis. DNA damage occurred in PLK1-depleted cells and inhibition of ATM (607585) strongly potentiated the lethality of PLK1 depletion. The data supported the notion that disruption of PLK1 function could be an important application in cancer therapy.

Yoo et al. (2004) showed that, during checkpoint response, Xenopus claspin (605434) becomes phosphorylated on thr906, creating a docking site for Plx1. This interaction promotes phosphorylation of claspin on ser934 by Plx1. Yoo et al. (2004) stated that, after a prolonged interphase arrest, aphidicolin-treated egg extracts typically undergo adaptation and enter into mitosis despite the presence of incompletely replicated DNA. In this process, claspin dissociates from chromatin, and Chk1 (603078) undergoes inactivation. By contrast, aphidicolin-treated extracts containing mutants of claspin with thr906-to-ala or ser934-to-ala substitutions were unable to undergo adaptation. Under such adaptation-defective conditions, claspin accumulated on chromatin at high levels, and Chk1 did not decrease in activity. These results indicated that the Plx1-dependent inactivation of claspin results in termination of a DNA replication checkpoint response.

Yoshida et al. (2006) found that in S. cerevisiae the small GTP-binding protein RhoA (165390) stimulates type 2 myosin contractility and formin (FMN1; 136535)-dependent assembly of the cytokinetic actin contractile ring. Yoshida et al. (2006) found that budding yeast Polo-like kinase Cdc5 controls the targeting and activation of RhoA at the division site via Rho1 guanine nucleotide exchange factors. Yoshida et al. (2006) concluded that this role of Cdc5 (Polo-like kinase) in regulating Rho1 is likely to be relevant to cytokinesis and asymmetric cell division in other organisms.

Petronczki et al. (2007) stated that localization of ECT2 (600586) to the central spindle at anaphase promotes local activation of RhoA GTPase (165390), which induces assembly and ingression of the contractile ring. They showed that PLK1 functioned in the same pathway to initiate cytokinesis. Inhibition of PLK1 in HeLa cells abolished interaction of ECT2 with its activator and midzone anchor, CYK4 (RACGAP1; 604980), thereby preventing localization of ECT2 to the central spindle and leading to early cytokinesis defects.

Wang et al. (2007) showed that Drosophila Polo, a key cell cycle regulator, the mammalian counterparts of which have been implicated as oncogenes as well as tumor suppressors, acts as a tumor suppressor in the larval brain. Supernumerary neuroblasts are produced at the expense of neurons in polo mutants. Polo directly phosphorylates partner of Numb (Pon), a Drosophila adaptor protein for Numb (see 603728), and this phosphorylation event is important for Pon to localize Numb. In Polo mutants, the asymmetric localization of Pon, Numb, and atypical protein kinase C are disrupted, whereas other polarity markers are largely unaffected. Overexpression of Numb suppresses neuroblast overproliferation caused by polo mutations, suggesting that Numb has a major role in mediating this effect of Polo. Wang et al. (2007) concluded that their results revealed a biochemical link between the cell cycle and the asymmetric protein localization machinery, and indicated that Polo can inhibit progenitor self-renewal by regulating the localization and function of Numb.

Seki et al. (2008) reported that the synergistic action of BORA (610510) and kinase Aurora A (603072) controls the G2-M transition. BORA accumulates in the G2 phase and promotes Aurora A-mediated activation of PLK1, leading to the activation of cyclin-dependent kinase-1 (CDK1; 116940) and mitotic entry. Mechanistically, BORA interacts with PLK1 and controls the accessibility of its activation loop for phosphorylation and activation by Aurora A. Thus, Seki et al. (2008) concluded that BORA and Aurora A control mitotic entry.

Macurek et al. (2008) demonstrated that in human cells PLK1 activation occurs several hours before entry into mitosis, and requires Aurora A-dependent phosphorylation of thr210. They found that Aurora A can directly phosphorylate PLK1 on thr210, and that activity of Aurora A toward PLK1 is greatly enhanced by BORA, a known cofactor for Aurora A. Macurek et al. (2008) showed that BORA/Aurora-A-dependent phosphorylation is a prerequisite for PLK1 to promote mitotic entry after a checkpoint-dependent arrest. Importantly, expression of a PLK1-T210D phosphomimicking mutant partially overcame the requirement for Aurora A in checkpoint recovery. Macurek et al. (2008) concluded that taken together, their data demonstrated that the initial activation of PLK1 is a primary function of Aurora A.

Condensation of chromosomes during mitosis is promoted by condensin (see 611230), an evolutionarily conserved multisubunit ATPase. Using budding yeast, St-Pierre et al. (2009) showed that condensin was regulated by phosphorylation specifically in anaphase and that this phosphorylation required Cdc5. Cdc5 directly phosphorylated all 3 yeast regulatory condensin subunits, resulting in hyperactivated condensin DNA-supercoiling activity.

Ikeda et al. (2012) found that depletion of FRY (614818) in HeLa cells via siRNA resulted in misalignment of chromosomes during mitosis due to centriole splitting. FRY knockdown reduced the kinase activity of PLK1 and reduced accumulation of thr210-phosphorylated PLK1 at spindle poles in mitotic cells. Mouse Fry interacted with PLK1 in vitro and in cells, and the 2 proteins colocalized to centrosomes in early mitosis. Mutation analysis revealed that the interaction was mediated by the C-terminal domain of Fry and the C-terminal polo-box domain of PLK1. The interaction increased the kinase activity of PLK1 and was dependent upon Fry phosphorylation by CDK1. Phosphorylated Fry also interacted with Aurora A, resulting in increased Aurora A-dependent phosphorylation of PLK1 thr210, but not global Aurora A activation. Ikeda et al. (2012) hypothesized that phosphorylated FRY functions in activation of PLK1, at least in part, by acting as a scaffold for interaction of Aurora A and PLK1.

Shen et al. (2013) found that knockdown of the centriolar satellite protein FOR20 (FOPNL; 617149) in synchronized HeLa cells caused a defect in S-phase progression and inhibited cell proliferation. During S phase, knockdown of FOR20 inhibited centrosomal localization of PLK1, but not other centrosome-associated proteins. In T98G human glioblastoma cells, PLK1 first associated with centrosomal gamma-tubulin (see 191135) and FOR20 at the G1/S transition, but FOR20 persistently localized to centrosomes throughout the cell cycle. Protein pull-down and immunoprecipitation analyses revealed that FOR20 interacted with PLK1 in vitro and in cultured cells. FOR20 and PLK1 interacted in later G1, S, G2, and M phases. Mutation analysis showed that conserved residues in PLK1, but not its kinase activity, were required for PLK1 centrosomal localization. Tethering of kinase-dead PLK1 to centrosomes reversed S-phase defects in FOR20-depleted cells. Shen et al. (2013) concluded that FOR20 targets PLK1 to centrosomes during mitosis and that PLK1 has a kinase-independent role in S-phase progression.

MIS18A (618137), a component of the MIS18 complex, localizes at the centromere from late telophase to early G1 phase and plays a priming role in CENPA (117139) depostion. Lee et al. (2017) found that MIS18A was phosphorylated at ser36 by Aurora B kinase (AURKB; 604970) during mitosis in HeLa cells. MIS18A phosphorylation by Aurora B kinase was necessary for faithful segregation of chromosomes during mitosis, but it was not crucial for MIS18A centromere localization or CENPA centromere loading. Knockdown experiments in HeLa cells showed that MIS18A was required for recruitment of PLK1 to kinetochore at early mitosis, and phosphorylation of MIS18A by Aurora B kinase was required for kinetochore localization of PLK1. Immunoprecipitation assays in 293T cell extracts revealed that PLK1 bound via its polo box domain to phosphorylated MIS18A, and this binding enhanced PLK1 recruitment to kinetochore at prometaphase.

▼ Animal Model
To identify the source of newly formed cardiomyocytes during zebrafish heart regeneration, Jopling et al. (2010) established a genetic strategy to trace the lineage of cardiomyocytes in the adult fish, on the basis of the Cre/lox system widely used in the mouse. They used this system to show that regenerated heart muscle cells are derived from the proliferation of differentiated cardiomyocytes. Furthermore, the proliferating cardiomyocytes undergo limited dedifferentiation characterized by the disassembly of their sarcomeric structure, detachment from one another, and the expression of regulators of cell-cycle progression. Specifically, Jopling et al. (2010) showed that the gene product of polo-like kinase 1 (plk1) is an essential component of cardiomyocyte proliferation during heart regeneration. Jopling et al. (2010) concluded that their data provided the first direct evidence for the source of proliferating cardiomyocytes during zebrafish heart regeneration and indicated that stem or progenitor cells are not significantly involved in this process.

Tags: 16p12.2