{"doi":"10.1083/jcb.147.5.1009","title":"Rac Downregulates Rho Activity","abstract":"<jats:p>Using biochemical assays to determine the activation state of Rho-like GTPases, we show that the guanine nucleotide exchange factor Tiam1 functions as a specific activator of Rac but not Cdc42 or Rho in NIH3T3 fibroblasts. Activation of Rac by Tiam1 induces an epithelial-like morphology with functional cadherin-based adhesions and inhibits migration of fibroblasts. This epithelial phenotype is characterized by Rac-mediated effects on Rho activity. Transient PDGF-induced as well as sustained Rac activation by Tiam1 or V12Rac downregulate Rho activity. We found that Cdc42 also downregulates Rho activity. Neither V14Rho or N19Rho affects Rac activity, suggesting unidirectional signaling from Rac towards Rho. Downregulation of Rho activity occurs independently of Rac- induced cytoskeletal changes and cell spreading. Moreover, Rac effector mutants that are defective in mediating cytoskeleton changes or Jun kinase activation both downregulate Rho activity, suggesting that neither of these Rac signaling pathways are involved in the regulation of Rho. Restoration of Rho activity in Tiam1-expressing cells by expression of V14Rho results in reversion of the epithelioid phenotype towards a migratory, fibroblastoid morphology. We conclude that Rac signaling is able to antagonize Rho activity directly at the GTPase level, and that the reciprocal balance between Rac and Rho activity determines cellular morphology and migratory behavior in NIH3T3 fibroblasts.</jats:p>","journal":"The Journal of Cell Biology","year":1999,"id":670475,"datarank":1.0096527150723125,"base_score":6.731018100482083,"endowment":6.731018100482083,"self_citation_contribution":1.0096527150723125,"citation_network_contribution":0.0,"self_endowment_contribution":1.0096527150723125,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":837,"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":1751361,"name":"Jean P. ten Klooster","orcid":null,"position":1,"is_corresponding":false},{"id":1751362,"name":"Sanne van Delft","orcid":null,"position":2,"is_corresponding":false},{"id":1751365,"name":"Rob A. van der Kammen","orcid":null,"position":3,"is_corresponding":false},{"id":1751366,"name":"John G. 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Neither V14Rho or N19Rho affects Rac activity, suggesting unidirectional signaling from Rac towards Rho. Downregulation of Rho activity occurs independently of Rac- induced cytoskeletal changes and cell spreading. Moreover, Rac effector mutants that are defective in mediating cytoskeleton changes or Jun kinase activation both downregulate Rho activity, suggesting that neither of these Rac signaling pathways are involved in the regulation of Rho. Restoration of Rho activity in Tiam1-expressing cells by expression of V14Rho results in reversion of the epithelioid phenotype towards a migratory, fibroblastoid morphology. We conclude that Rac signaling is able to antagonize Rho activity directly at the GTPase level, and that the reciprocal balance between Rac and Rho activity determines cellular morphology and migratory behavior in NIH3T3 fibroblasts.</jats:p>","is_dataset_classified":null,"base_score":6.731018100482083,"endowment":6.731018100482083,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"10579721","pmcid":"PMC2169355","openalex_id":"https://openalex.org/W2112668385","authors":[],"funders":[],"total_grants":0,"fwci":17.4537,"citation_percentile":0.99665378,"influential_citations":0,"citation_trend":[{"year":2012,"count":35},{"year":2013,"count":47},{"year":2014,"count":33},{"year":2015,"count":23},{"year":2016,"count":21},{"year":2017,"count":16},{"year":2018,"count":15},{"year":2019,"count":14},{"year":2020,"count":11},{"year":2021,"count":18},{"year":2022,"count":9},{"year":2023,"count":12},{"year":2024,"count":6},{"year":2025,"count":8},{"year":2026,"count":2}],"oa_status":"bronze","license":null,"oa_locations":[{"url":"https://rupress.org/jcb/article-pdf/147/5/1009/1287586/9906039.pdf","host_type":"journal"},{"url":"https://rupress.org/jcb/article-pdf/147/5/1009/1287586/9906039.pdf","host_type":"publisher"},{"url":"https://rupress.org/jcb/article-pdf/147/5/1009/1853660/9906039.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1083/jcb.147.5.1009","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/10579721","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2169355","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC2169355","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC2169355?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Protein Kinase Regulation and GTPase Signaling","TGF-β signaling in diseases","Wnt/β-catenin signaling in development and cancer","3T3 Cells","Animals","Cadherins","Cell Adhesion","Cell Line","Cell Movement","Cytoskeleton","Down-Regulation","Epithelial Cells","GTP Phosphohydrolases","GTPase-Activating Proteins","Guanine Nucleotide Exchange Factors","Mice","Phenotype","Platelet-Derived Growth Factor","Protein Biosynthesis","Proteins","Signal Transduction","T-Lymphoma Invasion and Metastasis-inducing Protein 1","cdc42 GTP-Binding Protein","rac GTP-Binding Proteins"],"mesh_terms":["T-Lymphoma Invasion and Metastasis-inducing Protein 1","Animals","Cell Adhesion","Cell Line","Cell Movement","Cytoskeleton","Epithelial Cells","Phenotype","Platelet-Derived Growth Factor","Proteins","Protein Biosynthesis","Signal Transduction","Down-Regulation","Cadherins","3T3 Cells","GTP Phosphohydrolases","Guanine Nucleotide Exchange Factors","GTPase-Activating Proteins","rac GTP-Binding Proteins","cdc42 GTP-Binding Protein","Mice"],"keywords":["Guanine nucleotide exchange factor","CDC42","Cell biology","Downregulation and upregulation","Rac GTP-Binding Proteins","Biology","GTPase","RAC1","Cytoskeleton","Actin cytoskeleton","PAK1","Signal transduction","GTPase-activating protein","Actin","Activator (genetics)","Effector","Phenotype","Cell","G protein","Receptor","Biochemistry","Gene"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-15T22:14:09.023186Z","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":[]}