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The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

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The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities cancers Review The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities Jacopo Boni 1,2, Carlota Rubio-Perez 3 , Nuria López-Bigas 3,4, Cristina Fillat 2,5 and Susana de la Luna 1,2,4,6,* 1 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr Aiguader 88, 08003 Barcelona, Spain; [email protected] 2 Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain 3 Cancer Science Programme, Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain; [email protected] (C.R.-P.); [email protected] (N.L.-B.) 4 Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain 5 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036 Barcelona, Spain; cfi[email protected] 6 Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain * Correspondence: [email protected]; Tel.: +34-933-160-144 Received: 6 July 2020; Accepted: 27 July 2020; Published: 29 July 2020 Abstract: DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available. Keywords: DYRK kinases; cellular signaling; expression dysregulation; cell cycle; cell survival; tumor progression; kinase inhibitors 1. Background The first cancer gene identified, the proto-oncogene c-Src, was found to encode a protein kinase [1]. Yet, since then, almost a hundred kinase genes have been attributed a tumor suppressor or oncogenic role, and they represent the most abundant class of cancer driver genes known to date [2]. Dual-specificity tyrosine-regulated kinases (DYRKs) belong to the CMGC group of kinases, which includes cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), CDK-like kinases, the serine-arginine-rich protein kinase, Cdc2-like kinases (CLKs) and members of the RCK family [3]. The DYRK family is formed by three subfamilies: the DYRK subfamily, the homeodomain-interacting kinases (HIPKs), and the pre-messenger RNA-processing protein 4 kinases (PRP4Ks) [3]. Here, we will use “DYRK” to refer specifically to the DYRK subfamily, which contains five members in humans that are clustered into two classes based on their phylogenetic relationships [4]: Cancers 2020, 12, 2106; doi:10.3390/cancers12082106 www.mdpi.com/journal/cancers Cancers 2020, 12, x FOR PEER REVIEW 2 of 26 Cancers 2020, 12, 2106 2 of 26 kinases (PRP4Ks) [3]. Here, we will use “DYRK” to refer specifically to the DYRK subfamily, which contains five members in humans that are clustered into two classes based on their phylogenetic relationshipsclass I DYRKs, [4]: DYRK1Aclass I DYRKs, and DYRK1B DYRK1A (also and known DYRK1B as Mirk (also from known minibrain-related as Mirk from kinase) minibrain- and class relatedII DYRKs, kinase) DYRK2, and class DYRK3 II DYRKs, (also known DYRK2, as REDKDYRK3 from (also regulatory known erythroidas REDK kinase)from regulatory and DYRK4 erythroid(Figure 1kinase)A). and DYRK4 (Figure 1A). Figure 1. Dual-specificity tyrosine-regulated kinase (DYRK) protein kinases: primary structure and Figure 1. Dual-specificity tyrosine-regulated kinase (DYRK) protein kinases: primary structure and expression. (A) Scheme of the mammalian family of DYRKs, indicating their phylogenic relationships, expression. (A) Scheme of the mammalian family of DYRKs, indicating their phylogenic degree of homology and protein domains. The catalytic domain (KINASE) and the DYRK homology relationships, degree of homology and protein domains. The catalytic domain (KINASE) and the box (DH) are common to all members of the family. Class I DYRKs have two nuclear localization DYRK homology box (DH) are common to all members of the family. Class I DYRKs have two signals (NLSs) (NLS1 and NLS2) and a proline-, glutamic acid-, serine- and threonine-rich (PEST) nuclear localization signals (NLSs) (NLS1 and NLS2) and a proline-, glutamic acid-, serine- and motif. DYRK1A also includes a tract of 13 consecutive histidine residues (His) and a region enriched in threonine-rich (PEST) motif. DYRK1A also includes a tract of 13 consecutive histidine residues (His) serine/threonine residues (S/T) at the C-terminus. Class II DYRKs have a common structure, with the and a region enriched in serine/threonine residues (S/T) at the C-terminus. Class II DYRKs have a characteristic N-terminal autophosphorylation accessory (NAPA) domain at the N-terminus. In the common structure, with the characteristic N-terminal autophosphorylation accessory (NAPA) case of DYRK2 and DYRK4, functional NLSs have been described within the noncatalytic N-terminus. domain at the N-terminus. In the case of DYRK2 and DYRK4, functional NLSs have been described (B) The expression of human DYRKs based on the Genotype-Tissue Expression (GTEx) data represented within the noncatalytic N-terminus. (B) The expression of human DYRKs based on the Genotype- as the median TPMs (transcripts per million: GTEx Analysis Release V8, www.gtexportal.org/home, Tissue Expression (GTEx) data represented as the median TPMs (transcripts per million: GTEx dbGaP Accession phs000424.v8.p2). Tissues represented in the tumor data in Table S1 were chosen Analysis(brain: Release cortex; cervix:V8, www.gtexportal.org/home ectocervix; colon: sigmoid, dbGaP colon; esophagus;Accession mucosa,phs000424.v8.p2). kidney: cortex;Tissues skin: representedsuprapubic—not in the tumor sun-exposed). data in Table S1 were chosen (brain: cortex; cervix: ectocervix; colon: sigmoid colon; esophagus; mucosa, kidney: cortex; skin: suprapubic—not sun-exposed). DYRK kinases phosphorylate a broad set of substrates that are involved in a wide range of cellular processes,DYRK kinases and they phosphorylate are thought to a fulfill broad essential set of subs biologicaltrates functionsthat are involved both during in developmenta wide range and of in cellularmaintaining processes, homeostasis and they during are thethought adult life.to fulf Consequently,ill essentialthe biological aberrant regulationfunctions orboth expression during of developmentDYRK kinases and has in beenmaintaining associated homeostasis with several duri humanng the pathologies, adult life. includingConsequently, cancer. the In aberrant the present regulationarticle, we or willexpression review ourof understandingDYRK kinases ofhas the been role ofassociated DYRK family with membersseveral human in cancer pathologies, initiation and includingprogression, cancer. providing In the anpresent overview article, of thewe smallwill moleculesreview our that understanding act as DYRK inhibitorsof the role and of discussingDYRK familythe clinicalmembers implications in cancer initiation and therapeutic and progressio opportunitiesn, providing currently an available.overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently2. The available. DYRK Family of Kinases The members of the DYRK family all share a highly conserved catalytic domain with special 2. The DYRK Family of Kinases features within the CMGC group [5] and the so-called DYRK homology (DH) box motif located upstreamThe members of it (Figure of the1 A).DYRK In addition, family all DYRK share kinases a highly present conserved class-specific catalytic domains:domain with DYRK1A special and featuresDYRK1B within harbor the aCMGC proline-, group glutamic [5] and acid-, the serine- so-called and threonine-richDYRK homology (PEST) (DH) motif box in motif the noncatalytic located upstream of it (Figure 1A). In addition, DYRK kinases present class-specific domains: DYRK1A and Cancers 2020, 12, 2106 3 of 26 C-terminal region and equally positioned nuclear localization signals (NLS) (Figure1A). On the other hand, class II DYRKs present a N-terminal autophosphorylation accessory region (NAPA) domain, essential for catalytic activation [6] (Figure1A). All human DYRKs accumulate in the cytosol of cells, and DYRK1A, DYRK2 and DYRK4 can be imported into the nucleus by means of dedicated NLSs [7–9]. DYRK1A translocation to the nucleus acquires special biological significance, since it has been described as a chromatin-associated kinase capable of regulating the gene expression [10,11], and it is functionally linked to the DNA damage response (DDR) [12–14]. Chromatin association in the DDR context has also been recently described
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