Pseudokinase-converting mutation in protein kinase C alpha drives chordoid glioma by pathway rewiring

• 成果类型: Article
• 署名作者: Bellamy, Charlotte; Tovell, Hannah; Kao, Tiffany H.; Kornev, Alexandr; Letourneur, Quentin; Arslan, Janan; Schwaighofer, Selina; Baffi, Timothy R.; Dingli, Florent; Loew, Damarys; Lerond, Julie; Liva, Stephane; Izac, Brigitte; Andrieu, Muriel; Adle-Biassette, Homa; Barnier, Jean-Vianney; Stefan, Eduard; Taylor, Susan S.; Sanson, Marc; Newton, Alexandra C.; Bielle, Franck
• 署名单位: Centre National de la Recherche Scientifique (CNRS); Assistance Publique Hopitaux Paris (APHP); Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Hopital Universitaire Pitie-Salpetriere - APHP; University of California System; University of California San Diego; University of California System; University of California San Diego; Sorbonne Universite; Assistance Publique Hopitaux Paris (APHP); Centre for Eye Research Australia; University of Melbourne; Royal Victorian Eye & Ear Hospital; University of Innsbruck; University of Innsbruck; UNICANCER; Universite PSL; Institut Curie; Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Universite PSL; Institut Curie; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Lariboisiere-Fernand-Widal - APHP; Centre National de la Recherche Scientifique (CNRS); Universite Paris Saclay; Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Assistance Publique Hopitaux Paris (APHP); Institut National de la Sante et de la Recherche Medicale (Inserm); Hopital Universitaire Charles-Foix - APHP; Hopital Universitaire Pitie-Salpetriere - APHP; Assistance Publique Hopitaux Paris (APHP); Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Hopital Universitaire Charles-Foix - APHP; Hopital Universitaire Pitie-Salpetriere - APHP; Cornell University; Weill Cornell Medicine; Pfizer; Pfizer USA
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2524934123
• 发表日期: 2026-07-21
• 页码: e2524934123
• 关键词: Chordoid Glioma; PKCalpha; kinase; dominant-negative; pseudokinase; REGULATORY DOMAINS; neural progenitors; SERINE 879; phosphorylation; activation; tanycytes; junction; tumor; autoinhibition; 3rd-ventricle

摘要

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 (PKC alpha). The mutation is invariably an Asp to His substitution, suggesting a unique function beyond catalytic inactivation associated with other cancer-associated PKC alpha mutations. Here, we show that this mutation converts PKC alpha into a pseudokinase, abolishing catalytic activity, and, additionally, confers novel scaffolding functions. Activity assays in vitro and in cellulo revealed that PKC alpha D463H is catalytically inactive and functions as a dominant-negative to suppress endogenous PKC activity. Molecular dynamics simulations predicted that mutation to His, but not Asn, not only destabilizes the active site, but stabilizes the substrate-binding helices in the kinase C-lobe to potentially promote aberrant interactions. Supporting this, phosphoproteomic, proximity labeling, and coimmunoprecipitation mass spectrometry data from cells overexpressing PKC alpha D463H identified both altered phosphorylation of substrates and binding to multiple proteins involved in cell-cell junctions compared to WT enzyme. Last, single nuclei RNAseq established that ChG derives from specialized tanycytes. Our data reveal that this disease-defining, fully penetrant mutation converts PKC alpha into a pseudokinase with novel scaffold functions that uniquely rewire the cellular interactome to impair cell junction function.