{"doi":"10.7554/elife.94605.1","title":"FAK loss reduces BRAFV600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation","abstract":"<jats:p>Abstract</jats:p>\n                <jats:p>BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a “just-right” level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vill-Cre;BRAFV600E/+;Fakfl/fl mice, Fak deletion maximized BRAFV600E’s oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation resulted in increased mRNA expression and stability of Lgr4, promoting intestinal stemness and cecal tumor formation. Together, our findings show that a “just-right” ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.</jats:p>","journal":null,"year":null,"id":670384,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"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":904168,"name":"Huaibin Ge","orcid":"0000-0002-4726-7023","position":1,"is_corresponding":false},{"id":1751080,"name":"Shih-Fan Kuan","orcid":null,"position":2,"is_corresponding":false},{"id":628592,"name":"Chunhui Cai","orcid":"0000-0002-1742-4999","position":3,"is_corresponding":false},{"id":257792,"name":"Xinghua Lu","orcid":"0000-0002-8599-2269","position":4,"is_corresponding":false},{"id":495098,"name":"Farzad Esni","orcid":"0000-0002-0342-6862","position":5,"is_corresponding":false},{"id":218638,"name":"Robert E. Schoen","orcid":"0000-0001-7153-2766","position":6,"is_corresponding":false},{"id":282855,"name":"Jing Wang","orcid":"0000-0003-4343-2527","position":7,"is_corresponding":false},{"id":516391,"name":"Edward Chu","orcid":"0000-0002-0908-5325","position":8,"is_corresponding":false},{"id":1184718,"name":"Jing Hu","orcid":"0000-0001-7604-6732","position":9,"is_corresponding":false},{"id":961140,"name":"Chenxi Gao","orcid":"0009-0007-2312-382X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"FAK loss reduces BRAFV600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation","abstract":"<jats:p>Abstract</jats:p>\n                <jats:p>BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a “just-right” level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vill-Cre;BRAFV600E/+;Fakfl/fl mice, Fak deletion maximized BRAFV600E’s oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation resulted in increased mRNA expression and stability of Lgr4, promoting intestinal stemness and cecal tumor formation. Together, our findings show that a “just-right” ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19162232","pmcid":null,"openalex_id":"https://openalex.org/W4393910677","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"1R01CA236965-01A1","title":"Targeting PYK2 for the treatment of PDAC"},{"funder_name":"National Institutes of Health","grant_id":"5R01DK120698-04","title":"Chemical pancreatectomy for chronic pancreatitis and pancreatic cancer"},{"funder_name":"National Institutes of Health","grant_id":"5R21AI158824-02","title":"Evaluation of the Effect of Autoimmunity on Acinar-Derived Insulin Producing Cells"}],"total_grants":3,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://github.com/elifesciences/enhanced-preprints-data/raw/master/data/94605/v1/94605-v1.pdf","host_type":"journal"},{"url":"https://github.com/elifesciences/enhanced-preprints-data/raw/master/data/94605/v1/94605-v1.pdf","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/preprints/94605/elife-preprint-94605-v1.pdf","host_type":"publisher"},{"url":"https://cdn.elifesciences.org/preprints/94605/elife-preprint-94605-v1.xml","host_type":"publisher"},{"url":"https://elifesciences.org/reviewed-preprints/94605v1/pdf","host_type":"publisher"},{"url":"https://doi.org/10.7554/elife.94605.1","host_type":"journal"},{"url":"https://doi.org/10.7554/elife.94605.2","host_type":""},{"url":"https://doi.org/10.21203/rs.3.rs-2531119/v1","host_type":""},{"url":"https://doi.org/10.21203/rs.3.rs-2531119/v2","host_type":""},{"url":"https://doi.org/10.7554/elife.94605","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/36778401","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/38921956","host_type":""},{"url":"http://dx.doi.org/10.21203/rs.3.rs-2531119/v2","host_type":""},{"url":"http://dx.doi.org/10.7554/eLife.94605","host_type":""},{"url":"https://doaj.org/article/e2a122bab7f34dd78f4661a9fc648667","host_type":""}],"fields_of_study":["Melanoma and MAPK Pathways","Colorectal Cancer Treatments and Studies","Cellular Mechanics and Interactions","0301 basic medicine","03 medical and health sciences"],"mesh_terms":[],"keywords":["MAPK/ERK pathway","Cancer research","V600E","Phosphorylation","Focal adhesion","Carcinogenesis","Kinase","Downregulation and upregulation","Signal transduction","Tumor progression","Biology","Cell biology","Chemistry","Mutation","Cancer","Biochemistry","Genetics","Proto-Oncogene Proteins B-raf","Male","QH301-705.5","MAP Kinase Signaling System","EGFR","Science","Cecal Neoplasms","Article","Receptors, G-Protein-Coupled","Mice","BRAFV600E","Animals","Humans","Biology (General)","Extracellular Signal-Regulated MAP Kinases","Cancer Biology","FAK","Q","R","ErbB Receptors","ERK","Focal Adhesion Kinase 1","Medicine"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-15T21:48:43.398555Z","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":[]}