{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:17:01Z","timestamp":1792034221172,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013016","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000}}],"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","award":["fellowship"],"award-info":[{"award-number":["fellowship"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","award":["EOS ID: 30981113 and 40007527"],"award-info":[{"award-number":["EOS ID: 30981113 and 40007527"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["EOS ID: 30981113 and 40007527"],"award-info":[{"award-number":["EOS ID: 30981113 and 40007527"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002661","name":"Fonds De La Recherche Scientifique - FNRS","doi-asserted-by":"publisher","award":["PDR T.0154.23"],"award-info":[{"award-number":["PDR T.0154.23"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Loterie nationale belge","award":["via de Duve Institute"],"award-info":[{"award-number":["via de Duve Institute"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Proteins of pathogens such as cardioviruses, Kaposi sarcoma-associated herpes virus, varicella zoster virus and bacteria of the genus <jats:italic>Yersinia<\/jats:italic> were previously shown to use a common \u201cDDVF\u201d (D\/E-D\/E-V-F) short linear motif (SLiM) to hijack cellular kinases of the RSK (p90 ribosomal S6 kinases) family. Notably, the leader (L) protein of Theiler\u2019s murine encephalomyelitis virus (TMEV), a cardiovirus, and protein YopM of <jats:italic>Yersinia<\/jats:italic> species were shown to act as adapters to retarget RSKs toward unconventional substrates, nucleoporins and pyrin, respectively. Remarkable conservation of the SLiM docking site targeted by pathogens\u2019 proteins in RSK sequences suggested a physiological role for this site. Using SLiM prediction tools and AlphaFold docking, we screened the human proteome for proteins that would interact with RSKs through a DDVF-like SLiM. Co-immunoprecipitation experiments show that two candidates previously known as RSK partners, FGFR1 and SPRED2, as well as two candidates identified as novel RSK partners, GAB3 and CNKSR2 do interact with RSKs through a similar interface as the one used by pathogens, as was recently documented for SPRED2. FGFR1 employs a DSVF motif to bind RSKs and phosphorylation of the serine in this motif slightly increased RSK binding. FGFR1, SPRED2, GAB3 and CNKSR2 act upstream of RSK in the RAS-ERK MAP kinase pathway. Analysis of ERK activation in cells expressing a mutated form of RSK lacking the DDVF-docking site suggests that RSK might interact with the DDVF-like SLiM of several partners to provide a negative feed-back to the ERK MAPK pathway. Moreover, after TMEV infection, ERK phosphorylation was altered by the L protein in a DDVF-dependent manner. Taken together, our data suggest that, in addition to retargeting RSKs toward unconventional substrates, pathogens' proteins carrying a DDVF-like motif can compete with endogenous DDVF-containing proteins for RSK binding, thereby altering the regulation of the RAS-ERK MAP kinase pathway.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013016","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T21:19:21Z","timestamp":1743196761000},"page":"e1013016","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["The \u201cDDVF\u201d motif used by viral and bacterial proteins to hijack RSK kinases mimics a short linear motif (SLiM) found in proteins related to the RAS-ERK MAP kinase pathway"],"prefix":"10.1371","volume":"21","author":[{"given":"Martin","family":"Veinstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Stroobant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Wavreil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9615-8053","authenticated-orcid":true,"given":"Thomas","family":"Michiels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Sorgeloos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"ppat.1013016.ref001","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.virusres.2018.05.028","article-title":"Role of MAPK\/MNK1 signaling in virus replication","volume":"253","author":"R Kumar","year":"2018","journal-title":"Virus Res"},{"issue":"10","key":"ppat.1013016.ref002","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1515\/BC.2008.145","article-title":"RNA viruses and the mitogenic Raf\/MEK\/ERK signal transduction cascade","volume":"389","author":"S Pleschka","year":"2008","journal-title":"Biol Chem"},{"issue":"2","key":"ppat.1013016.ref003","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1042\/BJ20110289","article-title":"Regulation and function of the RSK family of protein kinases","volume":"441","author":"Y Romeo","year":"2012","journal-title":"Biochem J"},{"issue":"40","key":"ppat.1013016.ref004","doi-asserted-by":"crossref","first-page":"4823","DOI":"10.1038\/onc.2013.425","article-title":"RSK2 regulates endocytosis of FGF receptor 1 by phosphorylation on serine 789","volume":"33","author":"B Nadratowska-Wesolowska","year":"2014","journal-title":"Oncogene"},{"issue":"1","key":"ppat.1013016.ref005","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1042\/BJ20120938","article-title":"RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation","volume":"447","author":"M Saha","year":"2012","journal-title":"Biochem J"},{"issue":"6","key":"ppat.1013016.ref006","doi-asserted-by":"crossref","first-page":"104789","DOI":"10.1016\/j.jbc.2023.104789","article-title":"The ribosomal S6 kinase 2 (RSK2)-SPRED2 complex regulates the phosphorylation of RSK substrates and MAPK signaling","volume":"299","author":"J Lopez","year":"2023","journal-title":"J Biol Chem"},{"issue":"3","key":"ppat.1013016.ref007","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1021\/acs.jproteome.2c00505","article-title":"Phosphoproteomics profiling defines a target landscape of the basophilic protein kinases AKT, S6K, and RSK in skeletal myotubes","volume":"22","author":"AL Fricke","year":"2023","journal-title":"J Proteome Res"},{"issue":"2","key":"ppat.1013016.ref008","doi-asserted-by":"crossref","first-page":"dmm049107","DOI":"10.1242\/dmm.049107","article-title":"The RASopathies: from pathogenetics to therapeutics","volume":"15","author":"KE Hebron","year":"2022","journal-title":"Dis Model Mech"},{"issue":"9","key":"ppat.1013016.ref009","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nri3495","article-title":"Mitogen-activated protein kinases in innate immunity","volume":"13","author":"JS Arthur","year":"2013","journal-title":"Nat Rev Immunol"},{"issue":"3","key":"ppat.1013016.ref010","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/sj.onc.1202367","article-title":"Constitutive activation of the 41-\/43-kDa mitogen-activated protein kinase signaling pathway in human tumors","volume":"18","author":"R Hoshino","year":"1999","journal-title":"Oncogene"},{"issue":"1","key":"ppat.1013016.ref011","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1517\/14728222.2010.531014","article-title":"Paving the way for targeting RSK in cancer","volume":"15","author":"Y Romeo","year":"2011","journal-title":"Expert Opin Ther Targets"},{"issue":"7","key":"ppat.1013016.ref012","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines9070726","article-title":"RSK isoforms in acute myeloid leukemia","volume":"9","author":"M Youn","year":"2021","journal-title":"Biomedicines"},{"issue":"5","key":"ppat.1013016.ref013","doi-asserted-by":"crossref","first-page":"e2114647119","DOI":"10.1073\/pnas.2114647119","article-title":"A case of convergent evolution: several viral and bacterial pathogens hijack RSK kinases through a common linear motif","volume":"119","author":"F Sorgeloos","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"ppat.1013016.ref014","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/s41467-022-28109-x","article-title":"A non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host","volume":"13","author":"A Alexa","year":"2022","journal-title":"Nat Commun"},{"issue":"2","key":"ppat.1013016.ref015","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1399-0004.2006.00660.x","article-title":"Identification of novel mutations in the RSK2 gene (RPS6KA3) in patients with Coffin-Lowry syndrome","volume":"70","author":"JP Delaunoy","year":"2006","journal-title":"Clin Genet"},{"issue":"6","key":"ppat.1013016.ref016","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.sbi.2006.10.008","article-title":"Docking interactions in protein kinase and phosphatase networks","volume":"16","author":"A Rem\u00e9nyi","year":"2006","journal-title":"Curr Opin Struct Biol"},{"issue":"1","key":"ppat.1013016.ref017","doi-asserted-by":"crossref","first-page":"e10584","DOI":"10.15252\/msb.202110584","article-title":"Proteome-scale mapping of binding sites in the unstructured regions of the human proteome","volume":"18","author":"C Benz","year":"2022","journal-title":"Mol Syst Biol"},{"key":"ppat.1013016.ref018","article-title":"Pathogenic mutations of human phosphorylation sites affect protein-protein interactions","author":"T Rrustemi","year":"2023","journal-title":"bioRxiv"},{"key":"ppat.1013016.ref019","article-title":"Protein complex prediction with AlphaFold-Multimer","author":"R Evans","year":"2022","journal-title":"bioRxiv"},{"key":"ppat.1013016.ref020","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ymeth.2022.05.006","article-title":"Multi-level analysis of intrinsically disordered protein docking methods","volume":"204","author":"J Verburgt","year":"2022","journal-title":"Methods"},{"issue":"2","key":"ppat.1013016.ref021","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s44320-023-00005-6","article-title":"Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation","volume":"20","author":"CY Lee","year":"2024","journal-title":"Mol Syst Biol"},{"issue":"1","key":"ppat.1013016.ref022","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1038\/s41467-023-38015-5","article-title":"Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs","volume":"14","author":"F Mihali\u010d","year":"2023","journal-title":"Nat Commun"},{"issue":"7","key":"ppat.1013016.ref023","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1042\/EBC20220059","article-title":"Evolution of SLiM-mediated hijack functions in intrinsically disordered viral proteins","volume":"66","author":"J Glavina","year":"2022","journal-title":"Essays Biochem"},{"issue":"10","key":"ppat.1013016.ref024","doi-asserted-by":"crossref","first-page":"e13165","DOI":"10.1371\/journal.pone.0013165","article-title":"Yersinia virulence factor YopM induces sustained RSK activation by interfering with dephosphorylation","volume":"5","author":"M Hentschke","year":"2010","journal-title":"PLoS One"},{"issue":"W1","key":"ppat.1013016.ref025","doi-asserted-by":"crossref","first-page":"W464","DOI":"10.1093\/nar\/gkx238","article-title":"SLiMSearch: a framework for proteome-wide discovery and annotation of functional modules in intrinsically disordered regions","volume":"45","author":"I Krystkowiak","year":"2017","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"ppat.1013016.ref026","doi-asserted-by":"crossref","first-page":"D648","DOI":"10.1093\/nar\/gkab1006","article-title":"The IntAct database: efficient access to fine-grained molecular interaction data","volume":"50","author":"N Del Toro","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"ppat.1013016.ref027","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/pro.3978","article-title":"The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions","volume":"30","author":"R Oughtred","year":"2021","journal-title":"Protein Sci"},{"issue":"2","key":"ppat.1013016.ref028","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1083\/jcb.200905118","article-title":"Spred2 interaction with the late endosomal protein NBR1 down-regulates fibroblast growth factor receptor signaling","volume":"187","author":"FK Mardakheh","year":"2009","journal-title":"J Cell Biol"},{"issue":"2","key":"ppat.1013016.ref029","doi-asserted-by":"crossref","first-page":"303","DOI":"10.3390\/cells11020303","article-title":"Functions of CNKSR2 and its association with neurodevelopmental disorders","volume":"11","author":"H Ito","year":"2022","journal-title":"Cells"},{"issue":"19","key":"ppat.1013016.ref030","doi-asserted-by":"crossref","DOI":"10.3390\/ijms241914854","article-title":"Phosphorylation-assisted luciferase complementation assay designed to monitor kinase activity and kinase-domain-mediated protein-protein binding","volume":"24","author":"\u00c1 P\u00f3ti","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"10","key":"ppat.1013016.ref031","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nrm2509","article-title":"The RSK family of kinases: emerging roles in cellular signalling","volume":"9","author":"R Anjum","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"12","key":"ppat.1013016.ref032","doi-asserted-by":"crossref","first-page":"e1011042","DOI":"10.1371\/journal.ppat.1011042","article-title":"Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic","volume":"18","author":"B Lizcano-Perret","year":"2022","journal-title":"PLoS Pathog"},{"issue":"8","key":"ppat.1013016.ref033","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/s41590-020-0705-6","article-title":"Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis","volume":"21","author":"YH Park","year":"2020","journal-title":"Nat Immunol"},{"issue":"3","key":"ppat.1013016.ref034","doi-asserted-by":"crossref","first-page":"105739","DOI":"10.1016\/j.jbc.2024.105739","article-title":"Identification of RSK substrates using an analog-sensitive kinase approach","volume":"300","author":"B Lizcano-Perret","year":"2024","journal-title":"J Biol Chem"},{"issue":"1\u20133","key":"ppat.1013016.ref035","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-5793(02)02425-0","article-title":"The gift of Gab","volume":"515","author":"Y Liu","year":"2002","journal-title":"FEBS Lett"},{"issue":"3","key":"ppat.1013016.ref036","doi-asserted-by":"crossref","first-page":"dev200857","DOI":"10.1242\/dev.200857","article-title":"CNKSR2, a downstream mediator of retinoic acid signaling, modulates the Ras\/Raf\/MEK pathway to regulate patterning and invagination of the chick forebrain roof plate","volume":"150","author":"N Udaykumar","year":"2023","journal-title":"Development"},{"issue":"20","key":"ppat.1013016.ref037","doi-asserted-by":"crossref","first-page":"18514","DOI":"10.1074\/jbc.M301226200","article-title":"The yersinia virulence factor YopM forms a novel protein complex with two cellular kinases","volume":"278","author":"C McDonald","year":"2003","journal-title":"J Biol Chem"},{"issue":"10","key":"ppat.1013016.ref038","article-title":"Development of an ORF45-derived peptide to inhibit the sustained RSK activation and lytic replication of Kaposi\u2019s sarcoma-associated herpesvirus","volume":"93","author":"X Li","year":"2019","journal-title":"J Virol"},{"issue":"1","key":"ppat.1013016.ref039","first-page":"379","article-title":"Analysis of mutation in human cells by using an Epstein-Barr virus shuttle system","volume":"7","author":"RB DuBridge","year":"1987","journal-title":"Mol Cell Biol"},{"issue":"3","key":"ppat.1013016.ref040","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1017\/S1355838201002230","article-title":"Basis for regulated RNA cleavage by functional analysis of RNase L and Ire1p","volume":"7","author":"B Dong","year":"2001","journal-title":"RNA"},{"issue":"1","key":"ppat.1013016.ref041","doi-asserted-by":"crossref","first-page":"9188","DOI":"10.1038\/s41598-021-88610-z","article-title":"PKR activity modulation by phosphomimetic mutations of serine residues located three aminoacids upstream of double-stranded RNA binding motifs","volume":"11","author":"T Cesaro","year":"2021","journal-title":"Sci Rep"},{"issue":"2","key":"ppat.1013016.ref042","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/76095","article-title":"Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences","volume":"25","author":"A Follenzi","year":"2000","journal-title":"Nat Genet"},{"issue":"2","key":"ppat.1013016.ref043","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1006\/viro.1998.9134","article-title":"Adaptation of Theiler\u2019s virus to L929 cells: mutations in the putative receptor binding site on the capsid map to neutralization sites and modulate viral persistence","volume":"244","author":"K Jnaoui","year":"1998","journal-title":"Virology"},{"issue":"21","key":"ppat.1013016.ref044","doi-asserted-by":"crossref","first-page":"11223","DOI":"10.1128\/JVI.00829-09","article-title":"Random mutagenesis defines a domain of Theiler\u2019s virus leader protein that is essential for antagonism of nucleocytoplasmic trafficking and cytokine gene expression","volume":"83","author":"C Ricour","year":"2009","journal-title":"J Virol"},{"issue":"2","key":"ppat.1013016.ref045","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1002\/j.1460-2075.1992.tb05088.x","article-title":"Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein","volume":"11","author":"SJ Leevers","year":"1992","journal-title":"EMBO J"},{"key":"ppat.1013016.ref046","first-page":"531","article-title":"Protein identification and analysis tools in the ExPASy server","volume":"112","author":"MR Wilkins","year":"1999","journal-title":"Methods Mol Biol"},{"issue":"D1","key":"ppat.1013016.ref047","doi-asserted-by":"crossref","first-page":"D438","DOI":"10.1093\/nar\/gkac1065","article-title":"MobiDB: 10 years of intrinsically disordered proteins","volume":"51","author":"D Piovesan","year":"2023","journal-title":"Nucleic Acids Res"},{"issue":"W1","key":"ppat.1013016.ref048","doi-asserted-by":"crossref","first-page":"W11-5","DOI":"10.1093\/nar\/gkw265","article-title":"ProViz-a web-based visualization tool to investigate the functional and evolutionary features of protein sequences","volume":"44","author":"P Jehl","year":"2016","journal-title":"Nucleic Acids Res"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1013016","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013016","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T17:39:28Z","timestamp":1744306768000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013016"}},"subtitle":[],"editor":[{"given":"Nels C.","family":"Elde","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,3,28]]},"references-count":48,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1013016","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.ppat.1013016","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,28]]}}}