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Article (Published Version) Article Kinases and Cancer CICENAS, Jonas, et al. Abstract Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases [...]. Reference CICENAS, Jonas, et al. Kinases and Cancer. Cancers, 2018, vol. 10, no. 3 DOI : 10.3390/cancers10030063 PMID : 29494549 Available at: http://archive-ouverte.unige.ch/unige:105089 Disclaimer: layout of this document may differ from the published version. 1 / 1 cancers Editorial Kinases and Cancer Jonas Cicenas 1,2,3,* ID , Egle Zalyte 2, Amos Bairoch 4,5 ID and Pascale Gaudet 4,* 1 Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria 2 Proteomics Center, Institute of Biochemistry, Vilnius University Life Sciences Center, Sauletekio al. 7, LT-10257 Vilnius, Lithuania; [email protected] 3 MAP Kinase Resource, Bioinformatics, Melchiorstrasse 9, 3027 Bern, Switzerland 4 CALIPHO Group, SIB Swiss Institute of Bioinformatics, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland; [email protected] 5 Faculty of Medicine; University of Geneva; 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland * Correspondence: [email protected] (J.C.); [email protected] (P.G.); Tel.: +43-664-5875822 (J.C.) Received: 27 February 2018; Accepted: 28 February 2018; Published: 1 March 2018 Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases. Phosphorylation is one of the critical mechanisms for regulating different cellular functions, such as proliferation, cell cycle, apoptosis, motility, growth, differentiation, among others. Deregulation of kinase activity can result in dramatic changes in these processes. Moreover, deregulated kinases are frequently found to be oncogenic and can be central for the survival and spread of cancer cells [1]. There are several ways for kinases to become involved in cancers: mis-regulated expression and/or amplification, aberrant phosphorylation, mutation, chromosomal translocation, and epigenetic regulation. The CALIPHO group of the SIB Swiss Institute of Bioinformatics develops neXtProt, a knowledge base focused on human proteins [2]. CALIPHO has fully annotated 300 of the best characterized protein kinases with respect to their normal function and their role in disease and pathogenesis. It has generated a corpus of around 30,000 statements about each of these proteins. This data is being progressively integrated into the neXtProt database. As of February 2018, neXtProt has integrated the GO biological processes annotations captured in the framework of this project, representing both the signaling pathways in which each kinase is implicated, as well as the role of those pathways in higher level processes, such as apoptosis, cellular proliferation, and development. These functions may give insights into the mechanisms of pathogenesis of each different kinase. This first set of annotation comprises approximately 5000 different statements, extracted from over 5000 publications. In the neXtProt web interface, this data can be identified by the ‘Source’ set as neXtProt in the right-hand side of the annotation table visible on the neXtProt page for each entry (https://www.nextprot.org/) (see Figure1). Cancers 2018, 10, 63; doi:10.3390/cancers10030063 www.mdpi.com/journal/cancers Cancers 2018, 10, 63 2 of 7 Cancers 2018, 10, x FOR PEER REVIEW 2 of 7 Figure 1. The neXtProt function page for MAPK13 (https://www.nextprot.org/entry/NX_O15264/). Figure 1. The neXtProt function page for MAPK13 (https://www.nextprot.org/entry/NX_O15264/). Two datasets remain to be integrated: the first contains approximately 11,000 annotations describingTwo datasets the substrates remain and to bephosphorylation integrated: the sites first of containsthese substrates, approximately which can 11,000 provide annotations valuable describinginsight to identify the substrates potential and drug phosphorylation targets, or, importantly, sites of these predict substrates, undesirable which side can provideeffects. valuable insightThe to second identify dataset potential contains drug targets, close to or, 6,000 importantly, manually predict extracted undesirable annotations side of effects. great interest for cancerThe researchers: second dataset the containspotential close use toof 6000each manually kinase as extracted biomarkers annotations (prognostic, of great diagnostic, interest foror cancerpredictive); researchers: any reported the potential misregulatio use of eachn of kinase expression as biomarkers in disease, (prognostic, at the mRNA diagnostic, and/or or predictive);protein, or anyresulting reported from misregulation aberrant epigenetic of expression regulation; in disease, genetic at variants the mRNA associated and/or with protein, diseases, or resulting and finally, from aberrantthe use of epigenetic the protein regulation; kinase as genetica disease variants model. associated with diseases, and finally, the use of the proteinKinase kinase amplifications as a disease model. could be used as diagnostic, prognostic, and predictive biomarkers in variousKinase cancer amplifications types. The best could examples be used of as kinase diagnostic, gene amplifications prognostic, and could predictive be EGFR biomarkers in non-small in variouscell lung cancer [3], colorectal types. The [4], best bla examplesdder [5] pancreatic of kinase gene [6], and amplifications breast [7] cancers; could be ERBB2 EGFR inin non-smallbreast [8], cellesophageal lung [3], [9], colorectal gastric [10], [4], and bladder ovarian [5] pancreaticcancers [11]; [6 MET], and in breast on-small [7] cell cancers; lung ERBB2[12], gastric in breast [13], and [8], esophagealcolorectal cancers [9], gastric [14]; [10 ],and and AKT2 ovarian in cancerspancreatic [11]; MET[15] and in on-small ovarian cell cancers lung [12[16].], gastric Similarly, [13], andoverexpression colorectal cancersof mRNA [14 or]; protein and AKT2 kinases in pancreaticare very well [15 known] and in ovarian cancers cancers and used [16 as]. biomarker. Similarly, overexpressionAgain, EGFR [17], of mRNAERBB2 or[18], protein EPHA2 kinases [19], an ared veryAKT2 well [20] known could be in a cancers good example. and used as biomarker. Again,The EGFR phosphorylation [17], ERBB2 [ 18of ],some EPHA2 kina [ses,19], such and AKT2as EGFR [20 [21,22],] could ERBB2 be a good [21,23,24], example. ERK [25], AURKA [26],The p38 phosphorylation[27], and AKT [28,29] of some is associated kinases, with such prog asnosis EGFR in [cancers21,22], ERBB2and, in some [21,23 cases,,24], ERKis a better [25], AURKAmarker than [26], p38expression [27], and of AKT the [kinase.28,29] is In associated addition, with the prognosissubstrates inof cancers kinases and, are inknown some cases,to be isbiomarkers a better marker in various than cancers. expression For example of the kinase. SCH1 [30], In addition, p21Cip1 the[31], substrates p27Kip1 [32], of kinases androgen are receptor known to[33], be biomarkersand retinoblastoma in various protein cancers. (RB) For [34] example have been SCH1 shown [30], p21Cip1to be prognostic [31], p27Kip1 biomarkers [32], androgen in breast receptorand pancreatic [33], and cancer. retinoblastoma protein (RB) [34] have been shown to be prognostic biomarkers in breastOne and of pancreatic the most cancer.extreme paths to the cancer development and progression is the mutations of the variousOne of thegenes, most including extreme kinases. paths to The the mutated cancer development kinases can become and progression constitutively is the active mutations and thus of thecause various diverse genes, cellular including anomalies, kinases. leading The mutated to cancer kinases initiation can become or growth. constitutively Probably activethe most and well- thus causeknown diverse mutated cellular kinase anomalies, is BRAF, leading which tois cancerfrequently initiation mutated or growth. on Val-600 Probably (p.V600E) the most [35,36] well-known and is a mutateddriver mutation kinase is in BRAF, several which cancers, is frequently including mutatedcolorectal on cancer Val-600 [37], (p.V600E) melanoma [35 ,[37],36] andthyroid is a drivercancer mutation[38] and non-small in several cancers,cell lung includingcancer [39]. colorectal Other frequent cancer [mutations37], melanoma occur [37 in], KIT thyroid [40], cancerEGFR [41], [38] andand non-smallFTL3 [42]. cell lung cancer [39]. Other frequent mutations occur in KIT [40], EGFR [41], and FTL3 [42]. ChromosomalChromosomal translocationstranslocations cancan alsoalso bebe cancercancer drivers.drivers. TheThe mostmost well-knownwell-known translocationtranslocation createscreates what what is is known known as as the the Philadelphia Philadelphia chromosome, chromosome, it is it a is translocation a translocation that that creates creates a fusion a fusion of BCR of withBCR thewith ABL1 the tyrosineABL1 tyrosine kinase fusionkinase with fusion BCR with and BC theR subsequent and the subsequent constitutive constitutive activation ofactivation the kinase. of Aroundthe kinase. 95% Around of patients 95% with of patients chronic myelogenouswith chronic myelogenous leukemia have leukemia this abnormality have this [43 abnormality], as well as 25%[43], as well as 25% with acute lymphoblastic leukemia [44]. Another famous
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