A Catalytically Inactive Protein Kinase C alpha Mutation Drives Chordoid Glioma by Pathway Rewiring. uri icon

Overview

abstract

  • 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.

authors

  • Bellamy, Charlotte
  • Tovell, Hannah
  • Schwaighofer, Selina
  • Baffi, Timothy R
  • Arslan, Janan
  • Letourneur, Quentin
  • Dingli, Florent
  • Loew, Damarys
  • Kornev, Alexandr
  • Lerond, Julie
  • Kao, Tiffany H
  • Liva, Stephane
  • Izac, Brigitte
  • Andrieu, Muriel
  • Adle-Biassette, Homa
  • Barnier, Jean-Vianney
  • Stefan, Eduard
  • Sanson, Marc
  • Newton, Alexandra C
  • Bielle, Franck

publication date

  • May 31, 2025

Identity

PubMed Central ID

  • PMC12154579

Digital Object Identifier (DOI)

  • 10.1101/2025.05.30.657104

PubMed ID

  • 40501730