{"doi":"10.1101/2025.03.11.642495","title":"Characterization of MEK1/2 Degraders Uncovers a Kinase-Independent Role for MEK1/2 in the Stabilization and Maturation of CRAF","abstract":"Altered MAPK signaling frequently occurs in human disease. MEK1 and MEK2 (MEK1/2) are central protein kinases in the MAPK signaling cascade that phosphorylate ERK1/2 promoting cell growth. MEK1/2 degraders offer a strategy to characterize both kinase-dependent and independent functions of MEK1/2. Here, we discovered that MEK1/2 degradation, but not kinase inhibition, caused the subsequent degradation of upstream kinase CRAF via a cell-intrinsic mechanism. MEK1/2 binding to CRAF, but not MEK1/2 catalytic activity, was required for CRAF protein stability and maturation to a functional kinase. In the absence of MEK1/2, a minor pool of newly synthesized immature CRAF that had anti-apoptotic functions remained. Finally, we showed that a stable primed CRAF-MEK1/2 signaling complex existed in cells that required RAS binding to potentiate MEK-ERK phosphorylation. Together, we've discovered a previously unrecognized kinase-independent function of MEK1/2, while contextualizing MEK1/2 as an integral component of the CRAF activation cycle beyond the conventional CRAF-MEK kinase-substrate paradigm.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557417,"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":0.9591,"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":485100,"name":"Alison Kurimchak","orcid":"0000-0003-2608-0128","position":1,"is_corresponding":false},{"id":485101,"name":"Carlos Herrera-Montávez","orcid":"0000-0001-8586-7778","position":2,"is_corresponding":false},{"id":318659,"name":"Glenn A. Doyle","orcid":"0000-0003-3859-2470","position":3,"is_corresponding":false},{"id":1457636,"name":"Brandon D. Fox","orcid":null,"position":4,"is_corresponding":false},{"id":975476,"name":"Ishadi K. M. Kodikara","orcid":null,"position":5,"is_corresponding":false},{"id":401433,"name":"Xiaoping Hu","orcid":"0000-0001-7014-5983","position":6,"is_corresponding":false},{"id":337229,"name":"Jianping Hu","orcid":"0000-0002-6000-4922","position":7,"is_corresponding":false},{"id":228877,"name":"Jian Jin","orcid":"0000-0002-2387-3862","position":8,"is_corresponding":false},{"id":407669,"name":"James S. Duncan","orcid":"0000-0002-1276-2745","position":9,"is_corresponding":false},{"id":496336,"name":"Jason S. Wasserman","orcid":"0000-0002-0697-5971","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:55:17.435961Z","pmid":"40161716","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":[]}