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The Emerging Role of Polo-Like Kinase 1 in Epithelial-Mesenchymal Transition and Tumor Metastasis

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The Emerging Role of Polo-Like Kinase 1 in Epithelial-Mesenchymal Transition and Tumor Metastasis cancers Review The Emerging Role of Polo-Like Kinase 1 in Epithelial-Mesenchymal Transition and Tumor Metastasis Zheng Fu * ID and Donghua Wen Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-804-628-3843 Academic Editor: Joëlle Roche Received: 7 September 2017; Accepted: 25 September 2017; Published: 27 September 2017 Abstract: Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays a key role in the regulation of the cell cycle. PLK1 is overexpressed in a variety of human tumors, and its expression level often correlates with increased cellular proliferation and poor prognosis in cancer patients. It has been suggested that PLK1 controls cancer development through multiple mechanisms that include canonical regulation of mitosis and cytokinesis, modulation of DNA replication, and cell survival. However, emerging evidence suggests novel and previously unanticipated roles for PLK1 during tumor development. In this review, we will summarize the recent advancements in our understanding of the oncogenic functions of PLK1, with a focus on its role in epithelial-mesenchymal transition and tumor invasion. We will further discuss the therapeutic potential of these functions. Keywords: PLK1; EMT; tumor invasion and metastasis; drug resistance; cancer therapy 1. Introduction Polo-like kinases (PLKs) belong to the polo subfamily of serine/threonine kinases, which are highly evolutionarily conserved, from yeast to humans [1]. PLKs have emerged as important regulators for cell cycle progression, cell proliferation, differentiation, and adaptive responses (see reviews; [1–3]). The prototypic founding member of the family was identified in Drosophila melanogaster in 1988 and was named “Polo” since the knockout of the gene induced abnormal spindle poles during mitosis [4]. Only one Plk has been reported in the genomes of Drosophila (Polo), budding yeast (Cdc5) and fission yeast (Plo1) [2], whereas vertebrates have many PLK family members [2]. In humans, five PLK members (PLK1-PLK5) have been identified and exhibit differential tissue distributions and distinct functions with no or partial overlap in substrates [1,2,5,6] (Figure1). Among the human PLKs, PLK1 has been most extensively studied. Sharing a similar domain topology with other PLKs, full-length PLK1 is composed of an N-terminal serine/threonine kinase domain and the characteristic polo-box domain (PBD) in the C-terminus [7] (Figure1). The PBD is comprised of two polo boxes, polo box 1 and polo box 2, which fold together to form a functional PBD. The PBD binds phosphorylated serine/threonine motifs in PLK1’s substrates. The optimal binding motif of its substrates is Ser-[pSer/pThr]-[Pro/X], in which X represents any amino acid [8,9]. By binding with such motifs on its substrates, the PBD brings the enzyme to an array of substrates found at different subcellular structures, including centrosomes, kinetochores, the mitotic spindle, and the midbody. This confers diversity to PLK1’s function and allows exquisite regulation of the cell cycle [2,10]. A PBD mutant (H538A, K540M) that is deficient in phospho-binding delocalizes PLK1 and disrupts its function [11]. PLK1 also interacts with some of its Cancers 2017, 9, 131; doi:10.3390/cancers9100131 www.mdpi.com/journal/cancers Cancers 2017, 9, 131 2 of 15 Cancers 2017, 9, 131 2 of 15 bindingits binding partners partners in a phospho-independentin a phospho-independent or PBD-independent or PBD-independent manner. manner. For instance, For instance, aurora borealis aurora (Bora),borealis aurora (Bora), kinase aurora A activator,kinase A wasactivator, reported was to re beported capable to ofbe bindingcapable toof abinding PLK1 deletion to a PLK1 mutant deletion that lacksmutant the that PBD lacks [12]. Inthe addition PBD [12]. to theIn roleaddition of the to PBD the in role interacting of the PBD with in PLK1’s interacting substrates, with the PLK1’s PBD alsosubstrates, modulates the PBD PLK1’s also kinase modulates activity PLK1’s through kinase intramolecular activity through interaction intramolec [13,14ular]. The interaction PBD inhibits [13,14]. the kinaseThe PBD domain inhibits by reducingthe kinase its domain flexibility. by Reciprocally,reducing its theflexibility. kinase domainReciprocally, induces the a conformationalkinase domain alterationinduces a of conformational the PBD that renders alteration it less of capable the PBD of interactingthat renders with it less its binding capable targets. of interacting Phosphopeptide with its bindingbinding ortargets. activational Phosphopeptide phosphorylation binding of or the activation T210 residueal phosphorylation of PLK1 within of the the kinase T210 residue activation of PLK1 loop relieveswithin the the kinase inhibitory activation intramolecular loop relieves interaction the inhibitory [9,15]. intramolecular interaction [9,15]. FigureFigure 1.1. A schematic diagram illustrating the domain structures of the human polo-like kinase (PLK) familyfamily ofof proteins proteins (PLK1-5). (PLK1-5). The The number number of of amino amino acids acids in each in each family family member member is indicated is indicated on the on right. the Theright. location The location of the kinaseof the domainskinase domains is shown is inshow orange,n in orange, whereas whereas the polo-box the polo-box domains domains (PBD), made (PBD), of twomade polo-boxes of two polo-boxes (PB), are represented (PB), are represented in blue. These in blue. two domainsThese two are domains separated are by separated the interdomain by the linker,interdomain which compriseslinker, which a destruction comprises box a destructio (D-Box) indicatedn box (D-Box) in green. indicated The numbers in green. indicate The numbers the first andindicate the lastthe residuesfirst and ofthe these last domainsresidues of in these human domains PLKs. Residuesin human that PLKs. are Residues essential forthat ATP-binding are essential andfor enzymaticATP-binding activation and enzymatic (T-loop) within activation the kinase (T-loop) domains, within and forthe phosphoselectivity kinase domains, within and thefor polo-boxphosphoselectivity domains, arewithin depicted. the polo-box Sequence domains, identities withare depicted. the corresponding Sequence domains identities in PLK1with arethe providedcorresponding in percentages. domains in Two PLK1 distinct are provided strategies in for pe targetingrcentages. PLK1 Two aredistinct included: strategies ATP-competitive for targeting inhibitorsPLK1 are targetingincluded: the ATP-competitive catalytic activity inhibitors of PLK1, and targeting PBD-binding the catalytic antagonists activity competitively of PLK1, inhibitingand PBD- thebinding function antagonists of PBD. competitively inhibiting the function of PBD. PLK1PLK1 mediatesmediates almost almost every every stage stage of cell of division, cell di includingvision, including mitotic entry, mitotic centrosome entry, maturation,centrosome bipolarmaturation, spindle bipolar formation, spindle chromosome formation, chromosome congression congression and segregation, and segregation, mitotic exit, mitotic and cytokinesis exit, and cytokinesis execution [2]. In addition to its canonical role in mitosis and cytokinesis, recent studies suggest that PLK1 may have other important functions such as regulation of microtubule dynamics, Cancers 2017, 9, 131 3 of 15 Cancers 2017, 9, 131 3 of 15 execution [2]. In addition to its canonical role in mitosis and cytokinesis, recent studies suggest thatDNA PLK1 replication, may have chromosome other important dynamics, functions p53 activity, such as and regulation recovery of from microtubule DNA damage-induced dynamics, DNA G2 replication,arrest [16,17]. chromosome dynamics, p53 activity, and recovery from DNA damage-induced G2 arrestPLK1 [16,17 is]. overexpressed in a variety of human tumors, and its expression level often correlates withPLK1 increased is overexpressed cellular proliferation in a variety ofand human poor tumors,prognosis and in its cancer expression patients level often[18,19]. correlates It has withbeen increasedsuggested cellular that PLK1 proliferation controls and cancer poor developmen prognosis int cancerthrough patients multiple [18 ,19mechanisms]. It has been that suggested include that the PLK1canonical controls regulation cancer developmentof mitosis and through cytokinesis, multiple as mechanismswell as modulation that include of DNA the canonicalreplication regulation and cell ofsurvival mitosis [20,21]. and cytokinesis, However, as emerging well as modulation evidence sugg of DNAests replicationthat the oncogenic and cell survivalfunctions [20 of,21 PLK1]. However, extend emergingfar beyond evidence what suggestsis currently that theknown oncogenic [21]. functionsHere, we of will PLK1 discuss extend the far beyondrecent whatadvances is currently in the knownunderstanding [21]. Here, of PLK1 we will as discussan oncogene, the recent with advances a focus on in its the role understanding in epithelial-mesenchymal of PLK1 as an oncogene,transition with(EMT) a focus and ontumor its role invasion. in epithelial-mesenchymal We will further discuss transition the potential (EMT) and for tumor therapeutic invasion. targeting We will of further these discussnewly identified the potential oncogenic for therapeutic actions of targeting PLK1. of these
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