{"doi":"10.1146/annurev.immunol.18.1.143","title":"Negative Regulation of Cytokine Signaling Pathways","abstract":"<jats:p>The Janus family of protein tyrosine kinases (JAKs) and STAT transcription factors regulate cellular processes involved in cell growth, differentiation, and transformation through their association with cytokine receptors. The CIS family of proteins (also referred to as the SOCS or SSI family) has been implicated in the regulation of signal transduction by a variety of cytokines. Most of them appear to be induced after stimulation with several different cytokines, and at least three of them (CIS1, CIS3/SOCS3, and JAB/SOCS1) negatively regulate cytokine signal transduction by various means: CIS1 inhibits STAT5 activation by binding to cytokine receptors that recruit STAT5, whereas JAB/SOCS-1 and CIS3/SOCS-3 directly bind to the kinase domain of JAKs, thereby inhibiting tyrosine-kinase activity. Therefore, these CIS family members seem to function in a classical negative feedback loop of cytokine signaling. Biochemical characterization as well as gene disruption studies indicate that JAB/SOCS1/SSI-1 is an important negative regulator of interferon γ signaling. The mechanisms by which these inhibitors of cytokine signal transduction exert their effects have been extensively studied and will provide useful information for regulating tyrosine-kinase activity.</jats:p>","journal":"Annual Review of Immunology","year":2000,"id":681530,"datarank":0.9617727401564847,"base_score":6.411818267709897,"endowment":6.411818267709897,"self_citation_contribution":0.9617727401564847,"citation_network_contribution":0.0,"self_endowment_contribution":0.9617727401564847,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":608,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1780666,"name":"Atsuo Sasaki","orcid":null,"position":1,"is_corresponding":false},{"id":700204,"name":"Akihiko Yoshimura","orcid":"0000-0001-5676-8949","position":2,"is_corresponding":false},{"id":1737890,"name":"Hideo Yasukawa","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Negative Regulation of Cytokine Signaling Pathways","abstract":"<jats:p>The Janus family of protein tyrosine kinases (JAKs) and STAT transcription factors regulate cellular processes involved in cell growth, differentiation, and transformation through their association with cytokine receptors. The CIS family of proteins (also referred to as the SOCS or SSI family) has been implicated in the regulation of signal transduction by a variety of cytokines. Most of them appear to be induced after stimulation with several different cytokines, and at least three of them (CIS1, CIS3/SOCS3, and JAB/SOCS1) negatively regulate cytokine signal transduction by various means: CIS1 inhibits STAT5 activation by binding to cytokine receptors that recruit STAT5, whereas JAB/SOCS-1 and CIS3/SOCS-3 directly bind to the kinase domain of JAKs, thereby inhibiting tyrosine-kinase activity. Therefore, these CIS family members seem to function in a classical negative feedback loop of cytokine signaling. Biochemical characterization as well as gene disruption studies indicate that JAB/SOCS1/SSI-1 is an important negative regulator of interferon γ signaling. The mechanisms by which these inhibitors of cytokine signal transduction exert their effects have been extensively studied and will provide useful information for regulating tyrosine-kinase activity.</jats:p>","is_dataset_classified":null,"base_score":6.411818267709897,"endowment":6.411818267709897,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"10837055","pmcid":null,"openalex_id":"https://openalex.org/W2152000177","authors":[],"funders":[],"total_grants":0,"fwci":28.3263,"citation_percentile":0.99828627,"influential_citations":0,"citation_trend":[{"year":2012,"count":18},{"year":2013,"count":9},{"year":2014,"count":14},{"year":2015,"count":18},{"year":2016,"count":25},{"year":2017,"count":16},{"year":2018,"count":20},{"year":2019,"count":14},{"year":2020,"count":13},{"year":2021,"count":7},{"year":2022,"count":10},{"year":2023,"count":5},{"year":2024,"count":7},{"year":2025,"count":8},{"year":2026,"count":2}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://www.annualreviews.org/doi/pdf/10.1146/annurev.immunol.18.1.143","host_type":"publisher"},{"url":"https://doi.org/10.1146/annurev.immunol.18.1.143","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/10837055","host_type":"repository"}],"fields_of_study":["Cytokine Signaling Pathways and Interactions","Medicinal Plant Pharmacodynamics Research","Pharmacological Effects of Natural Compounds"],"mesh_terms":["Suppressor of Cytokine Signaling 1 Protein","Suppressor of Cytokine Signaling 3 Protein","Animals","Carrier Proteins","DNA-Binding Proteins","Humans","Protein-Tyrosine Kinases","Proteins","Repressor Proteins","Transcription Factors","Signal Transduction","Trans-Activators","Cytokines","src Homology Domains","Intracellular Signaling Peptides and Proteins","Suppressor of Cytokine Signaling Proteins"],"keywords":["SOCS3","Suppressor of cytokine signaling 1","Biology","Janus kinase","Janus kinase 1","Signal transduction","Suppressor of cytokine signalling","STAT5","Cell biology","SOCS2","Tyrosine kinase 2","JAK-STAT signaling pathway","Cytokine","Janus kinase 2","Cytokine receptor","SOCS5","Tyrosine kinase","Glycoprotein 130","Receptor","Immunology","Biochemistry","STAT3","Platelet-derived growth factor receptor","Growth factor","Gene"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T18:01:37.786598Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}