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New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome Leah J

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New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome Leah J Published OnlineFirst December 18, 2017; DOI: 10.1158/0008-5472.CAN-17-2291 Cancer Review Research New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome Leah J. Wilson1, Adam Linley2, Dean E. Hammond1, Fiona E. Hood1, Judy M. Coulson1, David J. MacEwan3, Sarah J. Ross4, Joseph R. Slupsky2, Paul D. Smith4, Patrick A. Eyers5, and Ian A. Prior1 Abstract The human protein kinome comprises 535 proteins that, with physiologic and pathologic mechanisms remain at least par- the exception of approximately 50 pseudokinases, control intra- tially obscure. By curating and annotating data from the liter- cellular signaling networks by catalyzing the phosphorylation ature and major public databases of phosphorylation sites, of multiple protein substrates. While a major research focus of kinases, and disease associations, we generate an unbiased the last 30 years has been cancer-associated Tyr and Ser/Thr resource that highlights areas of unmet need within the kinases, over 85% of the kinome has been identified to be kinome. We discuss strategies and challenges associated with dysregulated in at least one disease or developmental disorder. characterizing catalytic and noncatalytic outputs in cells, and Despite this remarkable statistic, for the majority of protein describe successes and new frontiers that will support more kinases and pseudokinases, there are currently no inhibitors comprehensive cancer-targeting and therapeutic evaluation in progressing toward the clinic, and in most cases, details of their the future. Cancer Res; 78(1); 1–15. Ó2017 AACR. Introduction families based on statistical sequence analysis (2). Since publi- cation of this groundbreaking census, further kinome-wide Protein kinases, which are nearly all members of the eukaryotic appraisal has been undertaken from a variety of research angles protein kinase (ePK) superfamily, represent a large and diverse (3–6). With recent estimates suggesting that phosphorylation family of enzymes that catalyze the context-dependent transfer of occurs on approximately 90% of proteins expressed in cultured the g-phosphate of ATP onto specific protein substrates. Modu- human cells (7), the contemporary relevance of kinome-wide lation of protein function by kinase-mediated phosphorylation of analysis remains extremely high. Furthermore, a recent wide- alcoholic amino acid side chains (Ser, Thr, and Tyr) underpins ranging protein phosphatase census confirms the presence of much of biological signaling, and kinase dysregulation is fre- 189 distinct human protein phosphatase genes (8). Together, quently associated with disease. Consequently, this protein super- protein kinases and phosphatases constitute an important regu- family has been the subject of increasingly intensive scrutiny ever latory force in signaling whose unequivocal medical relevance has since the first protein kinase activity (phosphorylase kinase) was now led to decades of successful pharmacologic intervention (9). characterized by Krebs and Fischer in 1955 (1). Important recent data also reveal widespread histidine phosphor- The first comprehensive survey of the human kinase comple- ylation in human cells, likely catalyzed by NME1 and 2 at ment by Manning and colleagues identified and classified 518 chemically distinct 1 and 3 positions of the imidazole ring to protein kinases, by grouping them into evolutionary related form chemically labile phosphoramidate bonds (10–12). This development implies the need for further technological inno- 1 vation to more comprehensively evaluate nonclassical cellular Department of Cellular and Molecular Physiology, Institute of Translational phosphorylation, while providing a timely reminder of the Medicine, University of Liverpool, Liverpool, United Kingdom. 2Department of Clinical Cancer Medicine, Institute of Translational Medicine, University of Liver- need for an unbiased analysis of poorly studied members of pool, Liverpool, United Kingdom. 3Department of Molecular and Clinical Phar- the human kinome to be prioritized. This will be important to macology, Institute of Translational Medicine, University of Liverpool, Liverpool, evaluate whether some of the newly annotated members of the United Kingdom. 4AstraZeneca, Cambridge Biomedical Campus, Cambridge, kinome, for example, NME3-9 are bona fide protein kinases or 5 United Kingdom. Department of Biochemistry, Institute of Integrative Biology, pseudokinases. University of Liverpool, Liverpool, United Kingdom. To support kinome analysis, several databases and online tools Note: Supplementary data for this article are available at Cancer Research have been designed to take advantage of the significant develop- Online (http://cancerres.aacrjournals.org/). ments in mass spectrometry–based technology and technical Corresponding Author: Ian A. Prior, Institute of Translational Medicine, Univer- advances in kinase–substrate identification (13, 14). Together, sity of Liverpool, Liverpool L69 3BX, United Kingdom. Phone: 4415-1794-5332; these now permit deeper knowledge of various aspects of kinase Fax: 4415-1794-4434; E-mail: [email protected] biology to be compiled and connected. However, a key issue for doi: 10.1158/0008-5472.CAN-17-2291 both expert and nonexpert users of such databases is a general Ó2017 American Association for Cancer Research. lack of kinase naming conformity, which does not permit easy www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst December 18, 2017; DOI: 10.1158/0008-5472.CAN-17-2291 Wilson et al. L A TLK GC A t y K p T C 2000 4000 Kinases A E M CK1 1000 3000 5000 T K S RGC r C e Figure 1. M h t G O C An overview of the protein kinome knowledgebase. The activity, cellular requirement, disease association, availability of protein structures and drugs, and research publications associated with each of the 535 members of the human protein kinome are displayed. Details and citations for sources of data are described in Supplementary Table S1. Activity pseudokinase pST pSH pTY pY Essential 1–5 cell lines ≥6 cell lines Disease Cancer Cancer & other Other 3D structure Structure(s) available Drugs FDA approved Ph. 3 Ph. 2 Ph. 1 Ro5 experimental Knowledge base Publications © 2017 American Association for Cancer Research comparative kinome analysis. Up-to-date information on kinome be further subclassified on the basis of primary sequence into physiology, disease association, and progress in therapeutic tar- seven major ePK families: TK, TKL, STE, CK1, AGC, CAMK, and geting can readily be obtained from public databases (Fig. 1; CMGC (2). Eighty-one of the ePK superfamily represent sub- Table 1; Supplementary Table S1). Such resources can also be branches of the kinome dendrogram that do not fit within the mined to evaluate specialized "niche" kinome data that might seven major groups and are classified as "Other" (2). The RGC be important for rarer cancers, a recent example being the complex kinase family, included in Fig. 1 and our datasets, has recently cellular landscape of mitosis-specific phospho-tyrosine (15). In been reclassified as a subgroup within the "Other" family this resource-based review, we have curated major insights from (KinBase: www.kinase.com). The remaining 56 non-ePK kinases these sources to provide a current, readily accessible, overview of within the kinome possess an atypical protein kinase domain that important aspects of human kinome biology. has little sequence similarity to the main kinase superfamily, and their classification into distinct kinase subfamilies is probably more appropriate (16). However, proteins within this atypical Kinome Biology group have verified, or are predicted to maintain, kinase activity The human kinome consists of 535 distinct protein kinases based on biochemical experiments and/or structural analysis (2). (Supplementary Table S1; KinBase: www.kinase.com). A total of Intriguingly, both the atypical and other kinase families have an 479 kinases contain a recognized ePK catalytic domain, which can over-representation of kinases shown to be essential in at least 6 of OF2 Cancer Res; 78(1) January 1, 2018 Cancer Research Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst December 18, 2017; DOI: 10.1158/0008-5472.CAN-17-2291 Human Protein Kinome Knowledgebase Table 1. Kinase databases and resources Kinome ontology/overview KinBASE http://www.kinase.com/ KinaseNET http://www.kinasenet.ca/ ProKinO http://vulcan.cs.uga.edu/prokino Phosphorylation/kinase-substrate resources GPS 3.0 http://gps.biocuckoo.org/ HPRD http://www.hprd.org/ Phospho.ELM http://phospho.elm.eu.org/ PHOSIDA http://141.61.102.18/phosida/index.aspx PhoshoNET http://www.phosphonet.ca/ PhosphoNetworks http://www.phosphonetworks.org/ PhosphoSitePlus https://www.phosphosite.org RegPhos 2.0 http://140.138.144.141/RegPhos/index.php Kinase drug sensitivity and affinity measurements canSAR 3.0 http://cansar.icr.ac.uk ChEMBL https://www.ebi.ac.uk/chembldb/ Drugbank https://www.drugbank.ca/ DrugKiNET http://www.drugkinet.ca/ Kinase SARfari https://www.ebi.ac.uk/chembl/sarfari/kinasesarfari International centre for kinase profiling http://www.kinase-screen.mrc.ac.uk/ Disease associations COSMIC http://cancer.sanger.ac.uk/cosmic DECIPHER http://diseases.jensenlab.org DISEASES https://decipher.sanger.ac.uk/ TCGA https://cancergenome.nih.gov/ UniProtKB http://www.uniprot.org/uniprot/ NOTE: Links to currently
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