{"doi":"10.1101/gad.14.11.1319","title":"<i>γ</i>-Catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of <i>β</i>-catenin","abstract":"<jats:p><jats:italic>β</jats:italic>-Catenin and <jats:italic>γ</jats:italic>-catenin (plakoglobin), vertebrate homologs of <jats:italic>Drosophila</jats:italic> armadillo, function in cell adhesion and the Wnt signaling pathway. In colon and other cancers, mutations in the APC tumor suppressor protein or<jats:italic>β</jats:italic>-catenin's amino terminus stabilize<jats:italic>β</jats:italic>-catenin, enhancing its ability to activate transcription of Tcf/Lef target genes. Though<jats:italic>β</jats:italic>- and <jats:italic>γ</jats:italic>-catenin have analogous structures and functions and like binding to APC, evidence that <jats:italic>γ</jats:italic>-catenin has an important role in cancer has been lacking. We report here that APC regulates both<jats:italic>β</jats:italic>- and <jats:italic>γ</jats:italic>-catenin and<jats:italic>γ</jats:italic>-catenin functions as an oncogene. In contrast to <jats:italic>β</jats:italic>-catenin, for which only amino-terminal mutated forms transform RK3E epithelial cells, wild-type and several amino-terminal mutated forms of <jats:italic>γ</jats:italic>-catenin had similar transforming activity. <jats:italic>γ</jats:italic>-Catenin's transforming activity, like <jats:italic>β</jats:italic>-catenin's, was dependent on Tcf/Lef function. However, in contrast to<jats:italic>β</jats:italic>-catenin, <jats:italic>γ</jats:italic>-catenin strongly activated c-<jats:italic>Myc</jats:italic> expression and c-Myc function was crucial for <jats:italic>γ</jats:italic>-catenin transformation. Our findings suggest <jats:italic>APC</jats:italic> mutations alter regulation of both<jats:italic>β</jats:italic>- and <jats:italic>γ</jats:italic>-catenin, perhaps explaining why the frequency of <jats:italic>APC</jats:italic> mutations in colon cancer far exceeds that of <jats:italic>β-catenin</jats:italic> mutations. Elevated c-Myc expression in cancers with APC defects may be due to altered regulation of both <jats:italic>β</jats:italic>- and<jats:italic>γ</jats:italic>-catenin. Furthermore, the data imply<jats:italic>β</jats:italic>- and <jats:italic>γ</jats:italic>-catenin may have distinct roles in Wnt signaling and cancer via differential effects on downstream target genes.</jats:p>","journal":"Genes &amp; Development","year":2000,"id":22338,"datarank":11.116721601082782,"base_score":5.4116460518550396,"endowment":5.4116460518550396,"self_citation_contribution":0.8117469077782561,"citation_network_contribution":10.304974693304526,"self_endowment_contribution":0.8117469077782561,"citer_contribution":10.304974693304526,"corpus_percentile":null,"corpus_rank":null,"citation_count":223,"citer_count":200,"citers_with_citation_signal":178,"citers_with_endowment":178,"datacite_reuse_total":2,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":140757,"name":"Barbara Kolligs","orcid":null,"position":1,"is_corresponding":false},{"id":140758,"name":"Karen M. Hajra","orcid":null,"position":2,"is_corresponding":false},{"id":140759,"name":"Gang Hu","orcid":null,"position":3,"is_corresponding":false},{"id":140760,"name":"Masachika Tani","orcid":null,"position":4,"is_corresponding":false},{"id":140761,"name":"Kathleen R. Cho","orcid":null,"position":5,"is_corresponding":false},{"id":37583,"name":"Eric R. Fearon","orcid":"0000-0003-2867-3971","position":6,"is_corresponding":false},{"id":140756,"name":"Frank T. Kolligs","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.4116460518550396,"endowment":5.4116460518550396,"datacite_reuse_total":2,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"10837025","pmcid":"PMC316666","openalex_id":"https://openalex.org/W1877472591","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"R01CA70097","title":null},{"funder_name":"NCI NIH HHS","grant_id":"T32 CA009676","title":null},{"funder_name":"NCI NIH HHS","grant_id":"T32CA09676-08","title":null}],"total_grants":3,"fwci":null,"citation_percentile":null,"influential_citations":7,"citation_trend":[{"year":2012,"count":10},{"year":2013,"count":8},{"year":2014,"count":4},{"year":2015,"count":4},{"year":2016,"count":4},{"year":2017,"count":5},{"year":2018,"count":3},{"year":2019,"count":3},{"year":2020,"count":2},{"year":2021,"count":4},{"year":2022,"count":2},{"year":2023,"count":10},{"year":2024,"count":1},{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"gold","license":null,"oa_locations":[{"url":"http://genesdev.cshlp.org/content/14/11/1319.full.pdf","host_type":"journal"},{"url":"http://genesdev.cshlp.org/content/14/11/1319.full.pdf","host_type":"GOLD"},{"url":"http://genesdev.cshlp.org/content/14/11/1319.full.pdf","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1101/gad.14.11.1319","host_type":"publisher"},{"url":"https://doi.org/10.1101/gad.14.11.1319","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/10837025","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/316666","host_type":"repository"}],"fields_of_study":["Wnt/β-catenin signaling in development and cancer","Cancer-related gene regulation","Hippo pathway signaling and YAP/TAZ","Biology","Medicine"],"mesh_terms":["Alleles","Animals","Cell Adhesion","Cell Division","Cell Line","Cell Line, Transformed","Colonic Neoplasms","Cytoskeletal Proteins","DNA-Binding Proteins","Fluorescent Antibody Technique","Gene Expression Regulation","Humans","Mice, Nude","Mutation","Neoplasm Transplantation","Neoplasms","Proto-Oncogene Proteins","Time Factors","Transcription Factors","Transcription, Genetic","Tumor Cells, Cultured","Signal Transduction","Trans-Activators","Proto-Oncogene Proteins c-myc","Adenomatous Polyposis Coli Protein","Zebrafish Proteins","Wnt Proteins","beta Catenin","Desmoplakins","gamma Catenin","Mice","Lymphoid Enhancer-Binding Factor 1"],"keywords":["Beta-catenin","Biology","Catenin","Wnt signaling pathway","Plakoglobin","Oncogene","Mutation","Cancer research","Adenomatous polyposis coli","Cell biology","Molecular biology","Signal transduction","Gene","Genetics","Cell cycle","Cancer","Colorectal cancer"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.24499320.v1","title":"Additional file 1 of LY6/PLAUR domain containing 3 (LYPD3) maintains melanoma cell stemness and mediates an immunosuppressive microenvironment","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24499320","title":"Additional file 1 of LY6/PLAUR domain containing 3 (LYPD3) maintains melanoma cell stemness and mediates an immunosuppressive microenvironment","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-06T19:36:26.847394Z","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,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}