{"doi":"10.1084/jem.20222056","title":"Somatic gain-of-function mutations in BUD13 promote oncogenesis by disrupting Fbw7 function","abstract":"Somatic mutations occurring on key enzymes are extensively studied and targeted therapies are developed with clinical promises. However, context-dependent enzyme function through distinct substrates complicated targeting a given enzyme. Here, we develop an algorithm to elucidate a new class of somatic mutations occurring on enzyme-recognizing motifs that cancer may hijack to facilitate tumorigenesis. We validate BUD13-R156C and -R230Q mutations evading RSK3-mediated phosphorylation with enhanced oncogenicity in promoting colon cancer growth. Further mechanistic studies reveal BUD13 as an endogenous Fbw7 inhibitor that stabilizes Fbw7 oncogenic substrates, while cancerous BUD13-R156C or -R230Q interferes with Fbw7Cul1 complex formation. We also find this BUD13 regulation plays a critical role in responding to mTOR inhibition, which can be used to guide therapy selections. We hope our studies reveal the landscape of enzyme-recognizing motif mutations with a publicly available resource and provide novel insights for somatic mutations cancer hijacks to promote tumorigenesis with the potential for patient stratification and cancer treatment.","journal":"The Journal of Experimental Medicine","year":2023,"id":375047,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"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":1137286,"name":"Xinyi Zhang","orcid":"0000-0002-2448-931X","position":1,"is_corresponding":false},{"id":225652,"name":"Xianming Tan","orcid":"0000-0002-5478-2269","position":2,"is_corresponding":false},{"id":484232,"name":"Pengda Liu","orcid":"0000-0003-2755-3601","position":3,"is_corresponding":false},{"id":660408,"name":"Jianfeng Chen","orcid":"0000-0001-9732-7461","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T01:16:19.336238Z","pmid":"37382881","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":[]}