{"database":"GPMDB","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":23,"searchCount":5},"additional":{"omics_type":["Other"],"submitter":["Putker M, et al."],"instrument_platform":["Instrument"],"disease":["Not Available"],"brenda_tissue":["Not available"],"species":["Homo_sapiens_viruses, Human"],"submitter_mail":["m.putker@umcutrecht.nl"],"publication":["25069953"],"model":["http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320002521","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320002469","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320002547","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320002573","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320002495"],"submitter_affiliation":["University Medical Center Utrecht, Molecular Cancer Research, Utrecht, Netherlands"],"cell_type":["Not available"],"repository":["GPMDB"],"pubmed_abstract":["We present evidence that FOXO3 and FOXO4 have acquired paralog-specific cysteines throughout vertebrate evolution. Using a proteome-wide screen, we identified previously unknown redox-dependent FOXO3 interaction partners. The nuclear import receptors Importin-7 (IPO7) and Importin-8 (IPO8) form a disulfide-dependent heterodimer with FOXO3, which is required for its reactive oxygen species-induced nuclear translocation. FOXO4 does not interact with IPO7 or IPO8.","Reduction-oxidation (redox) signaling, the translation of an oxidative intracellular environment into a cellular response, is mediated by the reversible oxidation of specific cysteine thiols. The latter can result in disulfide formation between protein hetero- or homodimers that alter protein function until the local cellular redox environment has returned to the basal state. We have previously shown that this mechanism promotes the nuclear localization and activity of the Forkhead Box O4 (FOXO4) transcription factor.","In this study, we sought to investigate whether redox signaling differentially controls the human FOXO3 and FOXO4 paralogs.","IPO7 and IPO8 control the nuclear import of FOXO3, but not FOXO4, in a redox-sensitive and disulfide-dependent manner. Our findings suggest that evolutionary acquisition of cysteines has contributed to regulatory divergence of FOXO paralogs, and that phylogenetic analysis can aid in the identification of cysteines involved in redox signaling.","Reduction-oxidation (redox) signaling, the translation of an oxidative intracellular environment into a cellular response, is mediated by the reversible oxidation of specific cysteine thiols. The latter can result in disulfide formation between protein hetero- or homodimers that alter protein function until the local cellular redox environment has returned to the basal state. We have previously shown that this mechanism promotes the nuclear localization and activity of the Forkhead Box O4 (FOXO4) transcription factor.In this study, we sought to investigate whether redox signaling differentially controls the human FOXO3 and FOXO4 paralogs.We present evidence that FOXO3 and FOXO4 have acquired paralog-specific cysteines throughout vertebrate evolution. Using a proteome-wide screen, we identified previously unknown redox-dependent FOXO3 interaction partners. The nuclear import receptors Importin-7 (IPO7) and Importin-8 (IPO8) form a disulfide-dependent heterodimer with FOXO3, which is required for its reactive oxygen species-induced nuclear translocation. FOXO4 does not interact with IPO7 or IPO8.IPO7 and IPO8 control the nuclear import of FOXO3, but not FOXO4, in a redox-sensitive and disulfide-dependent manner. Our findings suggest that evolutionary acquisition of cysteines has contributed to regulatory divergence of FOXO paralogs, and that phylogenetic analysis can aid in the identification of cysteines involved in redox signaling.","<h4>Unlabelled</h4>Reduction-oxidation (redox) signaling, the translation of an oxidative intracellular environment into a cellular response, is mediated by the reversible oxidation of specific cysteine thiols. The latter can result in disulfide formation between protein hetero- or homodimers that alter protein function until the local cellular redox environment has returned to the basal state. We have previously shown that this mechanism promotes the nuclear localization and activity of the Forkhead Box O4 (FOXO4) transcription factor.<h4>Aims</h4>In this study, we sought to investigate whether redox signaling differentially controls the human FOXO3 and FOXO4 paralogs.<h4>Results</h4>We present evidence that FOXO3 and FOXO4 have acquired paralog-specific cysteines throughout vertebrate evolution. Using a proteome-wide screen, we identified previously unknown redox-dependent FOXO3 interaction partners. The nuclear import receptors Importin-7 (IPO7) and Importin-8 (IPO8) form a disulfide-dependent heterodimer with FOXO3, which is required for its reactive oxygen species-induced nuclear translocation. FOXO4 does not interact with IPO7 or IPO8.<h4>Innovation and conclusion</h4>IPO7 and IPO8 control the nuclear import of FOXO3, but not FOXO4, in a redox-sensitive and disulfide-dependent manner. Our findings suggest that evolutionary acquisition of cysteines has contributed to regulatory divergence of FOXO paralogs, and that phylogenetic analysis can aid in the identification of cysteines involved in redox signaling."],"pubmed_title":["Evolutionary acquisition of cysteines determines FOXO paralog-specific redox signaling."],"pubmed_authors":["Putker Marrit M,Vos Harmjan R HR,van Dorenmalen Kim K,de Ruiter Hesther H,Duran Ana G AG,Snel Berend B,Burgering Boudewijn M T BM,Vermeulen Michiel M,Dansen Tobias B TB,","Putker Marrit M, Vos Harmjan R HR, van Dorenmalen Kim K, de Ruiter Hesther H, Duran Ana G AG, Snel Berend B, Burgering Boudewijn M T BM, Vermeulen Michiel M, Dansen Tobias B TB"],"name_synonyms":["biological signaling, signalling process, signaling process, single organism signaling., signalling"],"description_synonyms":["protein translation, transcription factor, T-cell leukemia, biological signaling, RGD1561201, nucleocytoplasm, Cysteine Hydrochloride, human being, L-Zystein, biosynthesis, broad, L-cysteine, Homo sapiense, Transcription Factor, FOXO3A, Homo spaiens, zinc ion regulated core promoter proximal region sequence-specific DNA binding, Homo sapien, responsivity, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, Homo sapians, establishment and maintenance of position, Impacts, establishment and maintenance of substrate location, Half-Cystine, sequence-specific DNA binding, Environmental Impacts, multicellular organismal biosynthetic process, protoplasm, reactivity, study, C76856, C, single-organism biosynthetic process, Transcription, Homo sapients, protoplast, formation, L Cysteine, anabolism, FOXO2, proteins, present in organism, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, man, synthesis, Environmental Impact, CYSTEINE, Homo sapience, RNA polymerase II proximal promoter sequence-specific DNA binding, signaling process, Homo sampiens, copper ion regulated proximal promoter sequence-specific DNA binding, Fkhr2, FREE CYSTEINE, C3H7NO2S, zinc ion regulated proximal promoter sequence-specific DNA binding, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, Half Cystine, (2R)-2-amino-3-mercaptopropanoic acid, Home sapiens, FKHRL1P2., single organism signaling, RNA polymerase II distal enhancer sequence-specific binding, establishment and maintenance of substance location, RNA polymerase II core promoter proximal region sequence-specific binding, FKHRL1, data, protein anabolism, protein biosynthetic process, wide/broad, Zinc Cysteinate, zinc ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, homeobox 1, function, Factor, metal ion regulated sequence-specific DNA binding RNA polymerase II transcription factor activity, Cys, results, FKHRL1P2, Impact, AFX1, transcription factor activity, Environmental, polypeptide, single organism localization, Experiment, Homo sapian, protein formation, RNA polymerase II transcription factor activity, protein biosynthesis, establishment and maintenance of localization, sequence-specific distal enhancer binding RNA polymerase II transcription factor activity, Vertebrate, internal to cell, Homo sapeins, 2010203A17Rik, (2R)-2-amino-3-sulfanylpropanoic acid, metal ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, Fkhrl1, AF6q21, Factors, MLLT7, AFX, Humo sapiens, L-2-Amino-3-mercaptopropionic acid, L-Cysteine, (R)-2-amino-3-mercaptopropanoic acid, single-organism localization, sequence-specific DNA binding RNA polymerase II transcription factor activity, metal ion regulated core promoter proximal region sequence-specific binding, copper ion regulated core promoter proximal region sequence-specific binding, Homo sapines, Transcription factor, human, signalling, L-Cystein, wide, Homo spiens, \"human\" EXACT genbank_common_name [], localisation, signalling process, protein synthesis, Foxo3a, Afxh, Environments, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, E920, afx, response, 1110048B16Rik, metal ion regulated sequence-specific DNA binding, Proteomes, metal ion regulated proximal promoter sequence-specific DNA binding, establishment and maintenance of cellular component location, Mllt7, sequence-specific transcription regulatory region DNA binding"],"pubmed_title_synonyms":["biological signaling, signalling process, signaling process, single organism signaling., signalling"],"pubmed_abstract_synonyms":["FKHRL1, RGD1561201, Pro Oxidants, wide/broad, broad, FOXO3A, FKHRL1P2, AFX1, C130009K11Rik, OM-1, 6230418K12Rik, Imp7, nuclear import, Active, C330016G14, Vertebrate, 2010203A17Rik, Oxygen Radicals, Fkhrl1, Ranbp8, Reactive, Ranbp7, Abcc10, Abcc10., AF6q21, C76856, FOXO2, MLLT7, AFX, present in organism, importin, Oxygen Species, single-organism nuclear import, Oxygen, single organism nuclear import, wide, MRP7, Foxo3a, Afxh, RANBP8, Fkhr2, RANBP7, Pro-Oxidants, afx, Om1, A330055O14Rik, substance nuclear import, TL, 1110048B16Rik, Active Oxygen, Proteomes, Mllt7"],"view_count":["23"],"citation_count":["0"],"search_count":["5"],"full_dataset_link":["http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320002469"],"search_domains":["dbgap_ncbi~0","patentfamilies~0","rfam~0","merops~0","complex-portal~0","uniprot~0","wormbaseparasite~0","embl-covid19~0","reactome~0","emdb~0","wgs_masters~0","ebiweb_resources~0","opentargets_genetics~0","biomodels_all~0","ipd-mhc~0","ebiweb_teams~0","taxonomy~0","genome_assembly~0","sc-experiments~0","ebiweb_people~0","enzymeportal_enzymes~0","ipd-nhkir~0","cellosaurus~0","pdbe~0","chebi~0","patentproteins~0","interpro7~0","uniref~0","chembl~0","pdbekb~0","gpcrdb~0","hgnc~0","sc-genes~0","intact~0","rhea~0","ebiweb_training~0","alphafold~0","imgt-hla~0","patentnucleotides~0","ensemblroot~0","eva_studies~0","non-coding~0","europepmc~0","pubmed~1","identifiers_registry~0","pdbechem~0","hpa-covid19~0","eva-variants-covid19~0","biosamples~0","gwas_catalog~0","biotools~0","tls_masters~0","mesh~0","coding~0","sra~0","opentargets~0","efo~0","embl-pathogen~0","project~0","pride~1","human_diseases~0","geo_datasets~0","embl~0","treefam~0","uniparc~0","ols~0","dgva~0","intenz~0","go~0","tsa_masters~0","biosamples-covid19~0","ebiweb_corporate~0","omim~0","lrg~0","earlycause-molecular-sequences~0","ipd-kir~0","empiar~0","rnacentral~0","orcid_data_claims~0","gpmdb~2","lineage-covid19~0","metagenomics~0","pfam~0","pride archive~1","varsite~0"],"reanalysis_count":["0"],"submitter_keywords":["Resource Reanalysis"],"citation_count_scaled":["0.0"],"reanalysis_count_scaled":["0.0"],"view_count_scaled":["0.007094386181369525"],"download_count_scaled":["0.0"],"normalized_connections":["1.0"],"additional_accession":[]},"is_claimable":false,"name":"Evolutionary Acquisition of Cysteines determines FOXO Paralog-Specific Redox Signaling","description":"Data from ProteomeXchange, PXD ID: PXD001018. Experiment: HRV_A, file: folder summary. Published as part of Antioxid Redox Signal. 2014 Jul 29  . From the Abstract: {{i}} Reduction-oxidation (redox) signaling, the translation of an oxidative intracellular environment into a cellular response, is mediated by the reversible oxidation of specific cysteine thiols. The latter can result in disulfide formation between protein hetero- or homodimers that alter protein function until the local cellular redox environment has returned to the basal state. We have previously shown that this mechanism promotes the nuclear localization and activity of the Forkhead Box O4 (FOXO4) transcription factor. Aims: in this study we sought to investigate whether redox signaling differentially controls the human FOXO3 and FOXO4 paralogs. Results: We present evidence that FOXO3 and FOXO4 have acquired paralog-specific cysteines throughout vertebrate evolution. Using a proteome-wide screen we identified previously unknown redox-dependent FOXO3 interaction partners ... {{/i}}","dates":{"submission":"2014-08-27"},"accession":"GPM32320002469","cross_references":{"pubmed":["25069953"],"Pride":["PXD001018"],"pride":[],"Pride Archive":["PXD001018"]}}