{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:13:30Z","timestamp":1792793610382,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008681","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000}}],"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R21CA231853"],"award-info":[{"award-number":["R21CA231853"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Tyrosine and serine\/threonine kinases are essential regulators of cell processes and are important targets for human therapies. Unfortunately, very little is known about specific kinase-substrate relationships, making it difficult to infer meaning from dysregulated phosphoproteomic datasets or for researchers to identify possible kinases that regulate specific or novel phosphorylation sites. The last two decades have seen an explosion in algorithms to extrapolate from what little is known into the larger unknown\u2014predicting kinase relationships with site-specific substrates using a variety of approaches that include the sequence-specificity of kinase catalytic domains and various other factors, such as evolutionary relationships, co-expression, and protein-protein interaction networks. Unfortunately, a number of limitations prevent researchers from easily harnessing these resources, such as loss of resource accessibility, limited information in publishing that results in a poor mapping to a human reference, and not being updated to match the growth of the human phosphoproteome. Here, we propose a methodological framework for publishing predictions in a unified way, which entails ensuring predictions have been run on a current reference proteome, mapping the same substrates and kinases across resources to a common reference, filtering for the human phosphoproteome, and providing methods for updating the resource easily in the future. We applied this framework on three currently available resources, published in the last decade, which provide kinase-specific predictions in the human proteome. Using the unified datasets, we then explore the role of study bias, the emergent network properties of these predictive algorithms, and comparisons within and between predictive algorithms. The combination of the code for unification and analysis, as well as the unified predictions are available under the resource we named KinPred. We believe this resource will be useful for a wide range of applications and establishes best practices for long-term usability and sustainability for new and existing predictive algorithms.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008681","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T01:46:57Z","timestamp":1612835217000},"page":"e1008681","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["KinPred: A unified and sustainable approach for harnessing proteome-level human kinase-substrate predictions"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9947-6484","authenticated-orcid":true,"given":"Bingjie","family":"Xue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2268-5226","authenticated-orcid":true,"given":"Benjamin","family":"Jordan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4223-318X","authenticated-orcid":true,"given":"Saqib","family":"Rizvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7146-9592","authenticated-orcid":true,"given":"Kristen M.","family":"Naegle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,8]]},"reference":[{"issue":"5","key":"pcbi.1008681.ref001","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.cell.2010.08.023","article-title":"Phosphotyrosine signaling: evolving a new cellular communication system","volume":"142","author":"WA Lim","year":"2010","journal-title":"Cell"},{"issue":"12","key":"pcbi.1008681.ref002","first-page":"139","article-title":"pHisphorylation; The Emergence of Histidine Phosphorylation as a Reversible Regulatory Modification","volume":"176","author":"SR Fuhs","year":"2017","journal-title":"Current opinion in cell biology"},{"key":"pcbi.1008681.ref003","article-title":"ProteomeScout: A repository and analysis resource for post-translational modifications and proteins","author":"MK Matlock","year":"2015","journal-title":"Nucleic Acids Research"},{"issue":"12","key":"pcbi.1008681.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0144692","article-title":"Reproducible Analysis of Post-Translational Modifications in Proteomes\u2014Application to Human Mutations","volume":"10","author":"AS Holehouse","year":"2015","journal-title":"PLoS ONE"},{"issue":"12","key":"pcbi.1008681.ref005","doi-asserted-by":"crossref","first-page":"3444","DOI":"10.1074\/mcp.O113.034181","article-title":"Status of Large-scale Analysis of Post-translational Modifications by Mass Spectrometry","volume":"12","author":"JV Olsen","year":"2013","journal-title":"Molecular & cellular proteomics: MCP"},{"key":"pcbi.1008681.ref006","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/scisignal.aau8645","article-title":"Illuminating the dark phosphoproteome","volume":"12","author":"EJ Needham","year":"2019","journal-title":"Sci Signal"},{"issue":"5","key":"pcbi.1008681.ref007","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nrd.2018.21","article-title":"Kinase inhibitors: the road ahead","volume":"17","author":"FM Ferguson","year":"2018","journal-title":"Nature Reviews Drug Discovery"},{"issue":"11","key":"pcbi.1008681.ref008","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0968-0004(00)89103-3","article-title":"Recognition and specificity in protein tyrosine kinase-mediated signalling","volume":"20","author":"Z Songyang","year":"1995","journal-title":"Trends in Biochemical Sciences"},{"issue":"3","key":"pcbi.1008681.ref009","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/S0960-9822(95)00060-1","article-title":"Evidence that SH2 domains promote processive phosphorylation by protein-tyrosine kinases","volume":"5","author":"BJ Mayer","year":"1995","journal-title":"Current biology: CB"},{"issue":"9","key":"pcbi.1008681.ref010","doi-asserted-by":"crossref","first-page":"3976","DOI":"10.1021\/ja211089v","article-title":"Rewiring kinase specificity with a synthetic adaptor protein","volume":"134","author":"EM Hobert","year":"2012","journal-title":"Journal of the American Chemical Society"},{"issue":"13","key":"pcbi.1008681.ref011","doi-asserted-by":"crossref","first-page":"3635","DOI":"10.1093\/nar\/gkg584","article-title":"Scansite 2.0: proteome-wide prediction of cell signaling interactions using short sequence motifs","volume":"31","author":"JC Obenauer","year":"2003","journal-title":"Nucleic Acids Research"},{"issue":"SUPPL16","key":"pcbi.1008681.ref012","first-page":"S2","article-title":"Incorporating substrate sequence motifs and spatial amino acid composition to identify kinase-specific phosphorylation sites on protein three-dimensional structures","volume":"14","author":"MG Su","year":"2013","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"pcbi.1008681.ref013","first-page":"2","article-title":"PKIS: Computational identification of protein kinases for experimentally discovered protein phosphorylation sites","volume":"14","author":"L Zou","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1008681.ref014","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2105-7-1","article-title":"PPSP: Prediction of PK-specific phosphorylation site with Bayesian decision theory","volume":"7","author":"Y Xue","year":"2006","journal-title":"BMC Bioinformatics"},{"key":"pcbi.1008681.ref015","article-title":"Prediction of kinase-specific phosphorylation sites through an integrative model of protein context and sequence","author":"R Patrick","year":"2016","journal-title":"Biochimica et Biophysica Acta\u2014Proteins and Proteomics"},{"issue":"16","key":"pcbi.1008681.ref016","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1093\/bioinformatics\/bty1051","article-title":"DeepPhos: Prediction of protein phosphorylation sites with deep learning","volume":"35","author":"F Luo","year":"2019","journal-title":"Bioinformatics"},{"issue":"4","key":"pcbi.1008681.ref017","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41587-019-0391-9","article-title":"Reconstructing kinase network topologies from phosphoproteomics data reveals cancer-associated rewiring","volume":"38","author":"M Hijazi","year":"2020","journal-title":"Nature Biotechnology"},{"issue":"2","key":"pcbi.1008681.ref018","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/bioinformatics\/btv550","article-title":"Positive-unlabeled ensemble learning for kinase substrate prediction from dynamic phosphoproteomics data","volume":"32","author":"P Yang","year":"2015","journal-title":"Bioinformatics"},{"issue":"268","key":"pcbi.1008681.ref019","doi-asserted-by":"crossref","first-page":"rs6","DOI":"10.1126\/scisignal.2003573","article-title":"Kinase-Substrate Enrichment Analysis Provides Insights into the Heterogeneity of Signaling Pathway Activation in Leukemia Cells","volume":"6","author":"P Casado","year":"2013","journal-title":"Science Signaling"},{"issue":"32","key":"pcbi.1008681.ref020","first-page":"1","article-title":"Using ProteomeScout: A Resource of Post-Translational Modifications, Their Experiments, and the Proteins That They Annotate","volume":"13","author":"AD Mooradian","year":"2017","journal-title":"Current Protocols in Bioinformatics"},{"key":"pcbi.1008681.ref021","doi-asserted-by":"crossref","unstructured":"Horn H, Schoof EM, Kim J, Robin X, Miller ML, Diella F, et al. KinomeXplorer: An integrated platform for kinome biology studies; 2014.","DOI":"10.1038\/nmeth.2968"},{"key":"pcbi.1008681.ref022","article-title":"GPS 5.0: An Update on the Prediction of Kinase-specific Phosphorylation Sites in Proteins","author":"C Wang","year":"2020","journal-title":"Genomics, Proteomics and Bioinformatics"},{"key":"pcbi.1008681.ref023","doi-asserted-by":"crossref","unstructured":"Real R, Vargas JM. The probabilistic basis of Jaccard\u2019s index of similarity; 1996.","DOI":"10.1093\/sysbio\/45.3.380"},{"issue":"24","key":"pcbi.1008681.ref024","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1093\/bioinformatics\/bty522","article-title":"Quokka: A comprehensive tool for rapid and accurate prediction of kinase family-specific phosphorylation sites in the human proteome","volume":"34","author":"F Li","year":"2018","journal-title":"Bioinformatics"},{"issue":"24","key":"pcbi.1008681.ref025","doi-asserted-by":"crossref","first-page":"3909","DOI":"10.1093\/bioinformatics\/btx496","article-title":"MusiteDeep: A deep-learning framework for general and kinase-specific phosphorylation site prediction","volume":"33","author":"D Wang","year":"2017","journal-title":"Bioinformatics"},{"key":"pcbi.1008681.ref026","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-642-86659-3","volume-title":"Evolution by Gene Duplication","author":"S Ohno","year":"1970"},{"issue":"9","key":"pcbi.1008681.ref027","doi-asserted-by":"crossref","first-page":"e0162579","DOI":"10.1371\/journal.pone.0162579","article-title":"High-Resolution Identification of Specificity Determining Positions in the LacI Protein Family Using Ensembles of Sub-Sampled Alignments","volume":"11","author":"R Sloutsky","year":"2016","journal-title":"Plos One"},{"key":"pcbi.1008681.ref028","first-page":"1","article-title":"Fine-tuning of substrate preferences of the Src-family kinase lck revealed through a high-throughput specificity screen","volume":"7","author":"NH Shah","year":"2018","journal-title":"eLife"},{"key":"pcbi.1008681.ref029","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.cell.2007.05.052","article-title":"Resource Systematic Discovery of In Vivo Phosphorylation Networks","volume":"129","author":"R Linding","year":"2007","journal-title":"Cell"},{"issue":"D1","key":"pcbi.1008681.ref030","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1093\/nar\/gks1094","article-title":"STRING v9.1: Protein-protein interaction networks, with increased coverage and integration","volume":"41","author":"A Franceschini","year":"2013","journal-title":"Nucleic Acids Research"},{"issue":"Database issue","key":"pcbi.1008681.ref031","doi-asserted-by":"crossref","first-page":"D261","DOI":"10.1093\/nar\/gkq1104","article-title":"Phospho.ELM: a database of phosphorylation sites\u2013update 2011","volume":"39","author":"H Dinkel","year":"2011","journal-title":"Nucleic acids research"},{"issue":"Database issue","key":"pcbi.1008681.ref032","doi-asserted-by":"crossref","first-page":"D261","DOI":"10.1093\/nar\/gkr1122","article-title":"PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse","volume":"40","author":"PV Hornbeck","year":"2012","journal-title":"Nucleic acids research"},{"issue":"Database issue","key":"pcbi.1008681.ref033","doi-asserted-by":"crossref","first-page":"D767","DOI":"10.1093\/nar\/gkn892","article-title":"Human Protein Reference Database\u20132009 update","volume":"37","author":"TSK Prasad","year":"2009","journal-title":"Nucleic acids research"},{"issue":"D1","key":"pcbi.1008681.ref034","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1093\/nar\/gks1158","article-title":"The BioGRID interaction database: 2013 Update","volume":"41","author":"A Chatr-Aryamontri","year":"2013","journal-title":"Nucleic Acids Research"},{"issue":"Database issue","key":"pcbi.1008681.ref035","first-page":"D295","article-title":"dbPTM 3.0: an informative resource for investigating substrate site specificity and functional association of protein post-translational modifications","volume":"41","author":"CT Lu","year":"2013","journal-title":"Nucleic acids research"},{"key":"pcbi.1008681.ref036","article-title":"UniProt: A worldwide hub of protein knowledge","author":"A Bateman","year":"2019","journal-title":"Nucleic Acids Research"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1008681","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008681","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T18:51:40Z","timestamp":1697827900000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008681"}},"subtitle":[],"editor":[{"given":"Arne","family":"Elofsson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,2,8]]},"references-count":36,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1008681","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1008681","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,8]]}}}