{"doi":"10.1172/jci.insight.168445","title":"Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation","abstract":"A T50I substitution in the K-Ras interswitch domain causes Noonan syndrome and emerged as a third-site mutation that restored the in vivo transforming activity and constitutive MAPK pathway activation by an attenuated KrasG12D,E37G oncogene in a mouse leukemia model. Biochemical and crystallographic data suggested that K-RasT50I increases MAPK signal output through a non-GTPase mechanism, potentially by promoting asymmetric Ras:Ras interactions between T50 and E162. We generated a \"switchable\" system in which K-Ras mutant proteins expressed at physiologic levels supplant the fms like tyrosine kinase 3 (FLT3) dependency of MOLM-13 leukemia cells lacking endogenous KRAS and used this system to interrogate single or compound G12D, T50I, D154Q, and E162L mutations. These studies support a key role for the asymmetric lateral assembly of K-Ras in a plasma membrane-distal orientation that promotes the formation of active Ras:Raf complexes in a membrane-proximal conformation. Disease-causing mutations such as T50I are a valuable starting point for illuminating normal Ras function, elucidating mechanisms of disease, and identifying potential therapeutic opportunities for Rasopathy disorders and cancer.","journal":"JCI Insight","year":2023,"id":371603,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":337815,"name":"Benjamin J. Huang","orcid":"0000-0001-6996-0833","position":1,"is_corresponding":false},{"id":1132127,"name":"Max Harris","orcid":null,"position":2,"is_corresponding":false},{"id":1131593,"name":"Christopher Boone","orcid":"0000-0001-5042-5654","position":3,"is_corresponding":false},{"id":1131594,"name":"Weijie Wang","orcid":"0000-0002-4509-5248","position":4,"is_corresponding":false},{"id":1132128,"name":"Heidi Carias","orcid":null,"position":5,"is_corresponding":false},{"id":1132129,"name":"Brian Mesiona","orcid":null,"position":6,"is_corresponding":false},{"id":1131595,"name":"Daniela Mavrici","orcid":"0000-0001-5843-423X","position":7,"is_corresponding":false},{"id":1132130,"name":"Amanda C. Kohler","orcid":null,"position":8,"is_corresponding":false},{"id":727608,"name":"Gideon Bollag","orcid":"0000-0002-1824-6194","position":9,"is_corresponding":false},{"id":493438,"name":"Chao Zhang","orcid":"0000-0002-8163-9716","position":10,"is_corresponding":false},{"id":1131596,"name":"Ying Zhang","orcid":"0000-0002-0839-5495","position":11,"is_corresponding":false},{"id":337819,"name":"Kevin Shannon","orcid":"0000-0003-4299-1773","position":12,"is_corresponding":false},{"id":1131592,"name":"Panyu Chen","orcid":"0000-0003-2174-954X","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T01:15:49.453761Z","pmid":"37681415","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":[]}