{"doi":"10.1016/j.jbc.2023.104786","title":"The adapter protein FADD provides an alternate pathway for entry into the cell cycle by regulating APC/C-Cdh1 E3 ubiquitin ligase activity","abstract":"The E3 ubiquitin ligase APC/C-Cdh1 maintains the G0/G1 state, and its inactivation is required for cell cycle entry. We reveal a novel role for Fas-associated protein with death domain (FADD) in the cell cycle through its function as an inhibitor of APC/C-Cdh1. Using real-time, single-cell imaging of live cells combined with biochemical analysis, we demonstrate that APC/C-Cdh1 hyperactivity in FADD-deficient cells leads to a G1 arrest despite persistent mitogenic signaling through oncogenic EGFR/KRAS. We further show that FADD WT interacts with Cdh1, while a mutant lacking a consensus KEN-box motif (FADD KEN ) fails to interact with Cdh1 and results in a G1 arrest due to its inability to inhibit APC/C-Cdh1. Additionally, enhanced expression of FADD WT but not FADD KEN , in cells arrested in G1 upon CDK4/6 inhibition, leads to APC/C-Cdh1 inactivation and entry into the cell cycle in the absence of retinoblastoma protein phosphorylation. FADD's function in the cell cycle requires its phosphorylation by CK1α at Ser-194 which promotes its nuclear translocation. Overall, FADD provides a CDK4/6-Rb-E2F-independent \"bypass\" mechanism for cell cycle entry and thus a therapeutic opportunity for CDK4/6 inhibitor resistance.","journal":"Journal of Biological Chemistry","year":2023,"id":353808,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"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":398506,"name":"Merna Sitto","orcid":null,"position":1,"is_corresponding":false},{"id":458935,"name":"Sundaresh Ram","orcid":"0000-0003-1828-9722","position":2,"is_corresponding":false},{"id":1100491,"name":"Wenbin Ji","orcid":"0000-0002-7667-9430","position":3,"is_corresponding":false},{"id":978126,"name":"Yajing Liu","orcid":"0000-0001-7148-6683","position":4,"is_corresponding":false},{"id":1100492,"name":"Raheema Damani","orcid":"0000-0001-7587-2442","position":5,"is_corresponding":false},{"id":411309,"name":"Dipankar Ray","orcid":"0000-0002-1297-2312","position":6,"is_corresponding":false},{"id":238049,"name":"Theodore S. Lawrence","orcid":"0000-0002-4186-8821","position":7,"is_corresponding":false},{"id":268396,"name":"Craig J. Galbán","orcid":"0000-0001-5596-7487","position":8,"is_corresponding":false},{"id":463495,"name":"Steven D. Cappell","orcid":"0000-0002-2885-7327","position":9,"is_corresponding":false},{"id":337050,"name":"Alnawaz Rehemtulla","orcid":"0000-0001-8291-3978","position":10,"is_corresponding":false},{"id":413466,"name":"Sahezeel Awadia","orcid":"0000-0003-4082-6985","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:13:02.680107Z","pmid":"37146968","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":[]}