{"doi":"10.1016/j.celrep.2023.113070","title":"TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation","abstract":"The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.","journal":"Cell Reports","year":2023,"id":334781,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"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":409522,"name":"Ziming Cheng","orcid":"0009-0006-4316-0903","position":1,"is_corresponding":false},{"id":947758,"name":"Hector Gonzalez-Cantú","orcid":null,"position":2,"is_corresponding":false},{"id":1064191,"name":"Matthew Rotondi","orcid":null,"position":3,"is_corresponding":false},{"id":360742,"name":"Gabriela Huelgas‐Morales","orcid":"0000-0002-9172-8253","position":4,"is_corresponding":false},{"id":947351,"name":"Purushoth Ethiraj","orcid":"0000-0002-0679-6041","position":5,"is_corresponding":false},{"id":493583,"name":"Zhijun Qiu","orcid":"0000-0001-8197-9975","position":6,"is_corresponding":false},{"id":1063693,"name":"Jonathan Lefkowitz","orcid":"0000-0001-9465-3333","position":7,"is_corresponding":false},{"id":424524,"name":"Wan Song","orcid":"0000-0003-4537-0454","position":8,"is_corresponding":false},{"id":947354,"name":"Bethany N. Landry","orcid":"0000-0002-7910-8326","position":9,"is_corresponding":false},{"id":947353,"name":"Hector L. Lopez","orcid":"0000-0003-0666-4222","position":10,"is_corresponding":false},{"id":719491,"name":"Cynthia M. Estrada-Zuniga","orcid":"0000-0002-2138-2517","position":11,"is_corresponding":false},{"id":1064192,"name":"Shivi Goyal","orcid":null,"position":12,"is_corresponding":false},{"id":1064193,"name":"Mohammad Aasif Khan","orcid":null,"position":13,"is_corresponding":false},{"id":1063694,"name":"Timothy J. Walker","orcid":"0000-0002-6146-3485","position":14,"is_corresponding":false},{"id":410598,"name":"Exing Wang","orcid":null,"position":15,"is_corresponding":false},{"id":377042,"name":"Faqian Li","orcid":"0000-0002-9954-095X","position":16,"is_corresponding":false},{"id":716582,"name":"Yanli Ding","orcid":"0000-0001-9554-0461","position":17,"is_corresponding":false},{"id":1063695,"name":"Lois M. Mulligan","orcid":"0000-0002-9308-8245","position":18,"is_corresponding":false},{"id":409524,"name":"Ricardo C.T. Aguiar","orcid":"0000-0002-8791-5849","position":19,"is_corresponding":false},{"id":399750,"name":"Patricia L. M. Dahia","orcid":"0000-0002-7757-370X","position":20,"is_corresponding":false},{"id":947352,"name":"Qianjin Guo","orcid":"0000-0002-0335-2381","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-19T01:09:53.742667Z","pmid":"37659079","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":[]}