{"doi":"10.17615/4cr5-sf81","title":"RHOAL57V drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling","abstract":"Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr<sup>42</sup>-to-Cys (Y42C) and Leu<sup>57</sup>-to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA<sup>Y42C</sup> exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA<sup>L57V</sup> promotes DGC growth. In mouse gastric organoids with deletion of <em>Cdh1</em>, which encodes the cell adhesion protein E-cadherin, the expression of RHOA<sup>L57V</sup>, but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA<sup>L57V</sup> also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA<sup>L57V</sup> retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr<sup>42</sup> and Leu<sup>57</sup> in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA<sup>L57V</sup> additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA<sup>Y42C</sup>. Our results reveal that RHOA<sup>L57V</sup> and RHOA<sup>Y42C</sup> drive the development of DGC through distinct biochemical and signaling mechanisms.","journal":"UNC Libraries","year":2025,"id":576026,"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":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":254947,"name":"Channing J. Der","orcid":"0000-0002-7751-2747","position":1,"is_corresponding":false},{"id":825884,"name":"J. Nathaniel Diehl","orcid":"0000-0002-7309-0903","position":2,"is_corresponding":false},{"id":1484157,"name":"Huynh, Minh V","orcid":"0000-0001-7349-7482","position":3,"is_corresponding":false},{"id":1484156,"name":"Rashid, Naim U","orcid":"0000-0002-0677-5283","position":4,"is_corresponding":false},{"id":35272,"name":"Adam J. Bass","orcid":"0000-0002-8193-4758","position":5,"is_corresponding":false},{"id":709829,"name":"Craig M. Goodwin","orcid":"0000-0003-1293-2334","position":6,"is_corresponding":false},{"id":25443,"name":"William C. Hahn","orcid":"0000-0003-2840-9791","position":7,"is_corresponding":false},{"id":254933,"name":"G. Aaron Hobbs","orcid":"0000-0002-4751-9681","position":8,"is_corresponding":false},{"id":449324,"name":"Adrienne D. Cox","orcid":"0000-0002-4901-2454","position":9,"is_corresponding":false},{"id":556033,"name":"Mariaelena Pierobon","orcid":"0000-0003-2084-1029","position":10,"is_corresponding":false},{"id":3015,"name":"Andrew J. Aguirre","orcid":"0000-0002-0701-6203","position":11,"is_corresponding":false},{"id":666712,"name":"Antje Schaefer","orcid":"0000-0002-2716-9899","position":12,"is_corresponding":false},{"id":226208,"name":"Emanuel F. Petricoin","orcid":"0000-0001-9146-5572","position":13,"is_corresponding":false},{"id":752358,"name":"Richard G. Hodge","orcid":"0000-0002-1920-1385","position":14,"is_corresponding":false},{"id":844166,"name":"Sehrish Javaid","orcid":"0000-0001-8092-9466","position":15,"is_corresponding":false},{"id":904147,"name":"Feifei Zhang","orcid":"0000-0002-9507-1682","position":16,"is_corresponding":false},{"id":1032091,"name":"Julien Dilly","orcid":"0000-0002-4006-5285","position":17,"is_corresponding":false},{"id":1098117,"name":"K M Guthrie","orcid":null,"position":18,"is_corresponding":false},{"id":825886,"name":"Elisa Baldelli","orcid":"0000-0002-6288-4599","position":19,"is_corresponding":false},{"id":1097691,"name":"Haisheng Zhang","orcid":"0000-0002-3696-7948","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:52.712371Z","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":[]}