International Journal of Molecular Sciences Review Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview Mattias F. Lindberg and Laurent Meijer * Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France; [email protected] * Correspondence: [email protected] Abstract: Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2- like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein ki- nases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, ho- mocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, demen- tia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in dia- betes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblas- Citation: Lindberg, M.F.; Meijer, L. tic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections Dual-Specificity, Tyrosine caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological Phosphorylation-Regulated Kinases implications calls for (1) a better understanding of the regulations and substrates of DYRKs and (DYRKs) and cdc2-Like Kinases CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation (CLKs) in Human Disease, an as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases Overview. Int. J. Mol. Sci. 2021, 22, and their implications in human disease. 6047. https://doi.org/10.3390/ ijms22116047 Keywords: DYRKs; CLKs; kinase; kinase inhibitor; Alzheimer’s disease; Down syndrome; type 1 diabetes; type 2 diabetes; acute lymphoblastic leukemia; viral infections Academic Editor: Ana Martínez Received: 30 April 2021 Accepted: 28 May 2021 1. Introduction Published: 3 June 2021 1.1. Protein Phosphorylation, Protein Kinases, Kinase Inhibitors, and Human Disease Publisher’s Note: MDPI stays neutral Protein phosphorylation is probably one of the most important and most studied with regard to jurisdictional claims in mechanism used by cells to regulate their proteins in terms of enzymatic activity, functions, published maps and institutional affil- localization, half-life, interactions with other proteins or other ligands, etc. It is also a key iations. mechanism for signal transduction between cells and within cells. Protein phosphorylation occupies a central place in the scientific literature with 337,916 references (as of 1 June 2021). Protein phosphorylation on serine, threonine, and tyrosine residues is carried out by protein kinases, a family of enzymes known as the human kinome, comprising at least Copyright: © 2021 by the authors. 538 members [1,2] divided into tyrosine kinases and serine/threonine kinases (some of the Licensee MDPI, Basel, Switzerland. latter are so-called dual specificity, as they also phosphorylate tyrosine residues), histidine This article is an open access article kinases, and pseudo-kinases (protein kinases: 573,472 references (as of 1 June 2021), i.e., distributed under the terms and one article published every 7 min for the last five years). Quite uniquely, four different conditions of the Creative Commons Nobel Prizes in medicine or physiology have been awarded to this field (1989, 1992, 2000, Attribution (CC BY) license (https:// 2001) (Figure1). creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 6047. https://doi.org/10.3390/ijms22116047 https://www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci. Sci. 20212021, ,2222, ,x 6047 FOR PEER REVIEW 22 of of 25 25 J. Michael BISHOP Harold E. VARMUS (Nobel 1989) Edwin G. KREBS Edmond H. FISCHER Protein Kinases (538) (Nobel 1992) Eric R. KANDEL Paul GREENGARD (Nobel 2000) Paul M. NURSE ATP ADP R. Timothy HUNT Leland H. HARTWELL (Nobel 2001) Phospho-protein Protein (pSer, pThr, pTyr) Figure 1. Figure 1. FourFour Nobel Nobel Prizes Prizes in inPhysiology Physiology or orMedicine Medicine awarded awarded in inthe the field field of protein of protein phosphory- phospho- lationrylation and and protein protein kinases. kinases. Protein Protein kinases kinases catalyze catalyze the transfer the transfer of the of γ the-phosphateγ-phosphate of ATP of ATPto the to hydroxylthe hydroxyl substituents substituents of serine, of serine, threonine, threonine, or tyrosine or tyrosine residues residues in proteins, in proteins, thereby thereby altering altering the physiologicalthe physiological properties properties of their of theirprotein protein substrates. substrates. The Thehuman human kinome kinome comprises comprises 538 protein 538 protein ki- nases.kinases. Michael Michael Bishop Bishop and and Harold Harold E. Varmus E. Varmus rece receivedived the theNobel Nobel Prize Prize 1989 1989 “for “for their their discovery discovery of theof thecellular cellular origin origin of retroviral of retroviral oncogenes” oncogenes” (src, (src, the thefirstfirst described described oncogene, oncogene, which which encodes encodes a ty- a rosinetyrosine kinase). kinase). Edmond Edmond H. H.Fischer Fischer and and Edwin Edwin G. G. Krebs Krebs received received the the Nobel Nobel Prize Prize 1992 1992 “for “for their their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism” discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism” (they are the true discoverers of protein kinases). The Nobel Prize 2000 was awarded jointly to (they are the true discoverers of protein kinases). The Nobel Prize 2000 was awarded jointly to Arvid Arvid Carlsson, Paul Greengard, and Eric R. Kandel “for their discoveries concerning signal transductionCarlsson, Paul in Greengard,the nervous and system” Eric R. Kandel(Paul Green “for theirgard discoveries investigated concerning the mechanism signal transduction of signal transductionin the nervous of system”neurotransmitters (Paul Greengard in the investigated central nervous the mechanism system and of signaldemonstrated transduction the key of neuro- im- portancetransmitters of phosphorylation in the central nervous by kinases system such and as demonstrated CDK5, PKA, the CK1, key and importance CK2 and of Eric phosphorylation Kandel the importanceby kinases suchof PKA as CDK5,in memory PKA, in CK1, Aplysia and). CK2 The andNobel Eric Prize Kandel 2001 the was importance awarded ofjointly PKA to in memoryLeland H. in Hartwell,Aplysia). TheTim NobelHunt, Prizeand Paul 2001 M. was Nurse awarded “for jointlytheir discoveries to Leland H.of Hartwell,key regulators Tim Hunt,of the andcell Paulcycle” M. (usingNurse yeast “for theiror sea discoveries urchin embryos, of key regulators they discovered of the cell how cycle” the (usingcell division yeast orcycle sea urchinis regulated embryos, by CDKs).they discovered For howmore the cell divisioninformation cycle is regulatedon each by CDKs).of Forthese more informationawardees, on eachsee: of https://www.nobelprize.org/prizes/medicine/ (accessed on 1 June 2021). these awardees, see: https://www.nobelprize.org/prizes/medicine/ (accessed on 1 June 2021). SinceSince protein protein phosphorylation phosphorylation is is involved involved in in essentially essentially all all physiological physiological events, events, abnormalabnormal phosphorylation phosphorylation is is implicated implicated in in many many human human diseases. diseases. Abnormally Abnormally expressed expressed oror abnormally abnormally active kinases representrepresent the the most most frequent frequent situation. situation. Consequently, Consequently, inhibiting inhib- itingdisease-relevant disease-relevant kinases kinases or normalizing or normalizing their activitiestheir activities constitutes constitutes a rational a rational approach ap- to proachtackle numerousto tackle numerous diseases. Thisdiseases. is why This protein is why kinases protein have kinases become, have in abecome, few decades in a afterfew decadestheir initial after discovery their [3initial], the firstdiscovery therapeutic [3], targets—before the first therapeutic G-protein-coupled targets—before receptors– G-protein-coupledin the pharmaceutical receptors–in industry’s the search pharmaceutical for novel drug industry’s candidates search (reviews: for [ 2novel,4–8]). drug As of candidatesearly February (reviews: 2021, 62[2,4–8]). kinase inhibitorsAs of early have February reached the2021, market, 62 kinase mostly forinhibitors the treatment have reachedof various thecancer market, indications mostly for [ 9the–11 treatmen]. t of various cancer indications [9–11]. 1.2.1.2. DYRKs DYRKs and and CLKs: CLKs: Structure, Structure, Acti Activation,vation, Interactors, Interactors, and and Substrates Substrates AmongAmong serine/threonine serine/threonine kinases, kinases, DYRKs DYRKs and and CLKs CLKs (Figures (Figures 2–4)2–4) belong