{"doi":"10.1101/2025.05.30.657104","title":"A Catalytically Inactive Protein Kinase C alpha Mutation Drives Chordoid Glioma by Pathway Rewiring","abstract":"Abstract Summary Chordoid glioma (ChG) is a rare, low-grade brain tumor characterized by a novel recurrent point mutation, D463H, in the kinase domain of protein kinase C alpha (PKCα). The mutation is invariably an Asp to His substitution, suggesting it endows a unique function beyond catalytic inactivation associated with other cancer-associated PKCα mutations. Here we use in vitro and in cellulo activity assays to show that PKCα D463H is catalytically inactive, functions as a dominant-negative mutant to suppress endogenous PKC and uniquely rewires the cellular interactome. Specifically, phosphoproteomic, proximity labeling, and co-immunoprecipitation mass-spectrometry data from cells overexpressing PKCα D463H identify altered phosphorylation of substrates and binding to multiple proteins involved in cell-cell junctions compared to WT enzyme. Lastly, single nuclei RNAseq reveals that ChG derives from specialized tanycytes. Our data suggest that this disease-defining, fully penetrant mutation promotes neomorphic non-catalytic scaffolding to impair cell junction function.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558115,"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":0.9619,"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":1458109,"name":"Hannah Tovell","orcid":"0000-0002-2473-7256","position":1,"is_corresponding":false},{"id":1458110,"name":"Selina Schwaighofer","orcid":"0009-0001-3273-7715","position":2,"is_corresponding":false},{"id":634360,"name":"Timothy R. Baffi","orcid":"0000-0003-2862-6155","position":3,"is_corresponding":false},{"id":1458111,"name":"Janan Arslan","orcid":"0000-0003-2683-3775","position":4,"is_corresponding":false},{"id":1458573,"name":"Quentin Letourneur","orcid":null,"position":5,"is_corresponding":false},{"id":272212,"name":"Florent Dingli","orcid":"0000-0002-7715-2446","position":6,"is_corresponding":false},{"id":272213,"name":"Damarys Loew","orcid":"0000-0002-9111-8842","position":7,"is_corresponding":false},{"id":381183,"name":"Alexandr P. Kornev","orcid":"0000-0002-1543-3795","position":8,"is_corresponding":false},{"id":891647,"name":"Julie Lerond","orcid":"0000-0002-9005-5771","position":9,"is_corresponding":false},{"id":1408051,"name":"Tiffany Kao","orcid":"0009-0007-8022-8169","position":10,"is_corresponding":false},{"id":1458574,"name":"Stéphane Liva","orcid":null,"position":11,"is_corresponding":false},{"id":1458112,"name":"Brigitte Izac","orcid":"0009-0004-5083-3681","position":12,"is_corresponding":false},{"id":557125,"name":"Muriel Andrieu","orcid":"0000-0003-0170-2250","position":13,"is_corresponding":false},{"id":654997,"name":"Homa Adle‐Biassette","orcid":"0000-0001-9446-8306","position":14,"is_corresponding":false},{"id":1458113,"name":"Jean‐Vianney Barnier","orcid":"0000-0002-2182-0900","position":15,"is_corresponding":false},{"id":634366,"name":"Eduard Stefan","orcid":"0000-0003-3650-4713","position":16,"is_corresponding":false},{"id":891653,"name":"Marc Sanson","orcid":"0000-0002-1813-8476","position":17,"is_corresponding":false},{"id":1614,"name":"Alexandra C. Newton","orcid":"0000-0002-2906-3705","position":18,"is_corresponding":false},{"id":891646,"name":"Franck Bielle","orcid":"0000-0001-6564-6388","position":19,"is_corresponding":false},{"id":1458572,"name":"Charlotte Bellamy","orcid":null,"position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40501730","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":[]}