{"doi":"10.1101/2025.10.12.681896","title":"The Wnt/APC destruction complex targets SREBP2 in a β-catenin-independent pathway to control cholesterol metabolism","abstract":"ABSTRACT APC, the core scaffold of the Wnt destruction complex, targets the transcriptional co-activator β-catenin for proteolysis. There is no convincing evidence that APC directs degradation of other substrates. Using a reconstituted cytosolic extract-based system and complementary in vivo and cellular assays, we show that SREBP2, the master regulator of cholesterol biosynthesis, is a direct APC–AXIN1 substrate. APC-dependent SREBP2 degradation is conserved in Xenopus embryos, mouse colon, and human colorectal cancer cells and restricts SREBP2 target-gene expression, cholesterol synthesis, and tissue cholesterol levels. Mechanistically, APC and AXIN1 promote SREBP2 degradation via a conserved phosphodegron, which marks SREBP2 for ubiquitination by the E3 enzyme, FBXW7. Like β-catenin, SREBP2 is stabilized by extracellular Wnt ligands; unlike β-catenin, its regulation is independent of GSK3β and CK1α and requires the entire APC mutational cluster region (MCR), whereas β-catenin turnover can operate with only a partial MCR. These findings define a β-catenin-independent branch of Wnt signaling that couples APC to sterol metabolism, providing a mechanistic rationale to target the mevalonate/SREBP2 axis in APC-mutant colorectal cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559287,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9554,"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":1264606,"name":"Cora E. Anderson","orcid":"0000-0001-9397-9534","position":1,"is_corresponding":false},{"id":1225132,"name":"William V. Trim","orcid":"0000-0002-5642-0608","position":2,"is_corresponding":false},{"id":1416815,"name":"Esteban Garita","orcid":"0000-0002-0334-658X","position":3,"is_corresponding":false},{"id":62832,"name":"Shinya Imada","orcid":null,"position":4,"is_corresponding":false},{"id":1379588,"name":"Saleh Khawaled","orcid":"0000-0002-2315-3697","position":5,"is_corresponding":false},{"id":787192,"name":"Heaji Shin","orcid":"0000-0001-5208-5999","position":6,"is_corresponding":false},{"id":244043,"name":"Jiuchun Zhang","orcid":null,"position":7,"is_corresponding":false},{"id":85448,"name":"Omer H. Yilmaz","orcid":"0000-0002-7577-4612","position":8,"is_corresponding":false},{"id":63534,"name":"Marc W. Kirschner","orcid":"0000-0001-6540-6130","position":9,"is_corresponding":false},{"id":1113293,"name":"Ahmed Rattani","orcid":"0000-0002-1058-7314","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:55:34.849815Z","pmid":"41279031","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":[]}