Disease-Defining Catalytically Inactive Protein Kinase C alpha Mutation is a Driver in Chordoid Glioma by Dominant-Negative Mechanism

This study demonstrates the role of this mutated kinase in the development of ChGs. Here we show the inactivation and dominant negative effect of PKCαD463H via in vitro and In cellulo activity assays.

Our results show the mutation affects the tertiary structure, resulting in an open, unstable protein. Phosphoproteomic and Co-Immunoprecipitation mass spectrometry data from HEK cells overexpressing PKC⍺D463H show decreased phosphorylation and interaction with proteins involved in cell adhesion. We confirm genetically through single nuclei RNAseq that ChGs derive from specialised tanycytes.