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The chordoid glioma PRKCA D463H mutation is a kinase inactive, gain-of-function allele that induces early-onset chondrosarcoma in mice.

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Title: The chordoid glioma PRKCA D463H mutation is a kinase inactive, gain-of-function allele that induces early-onset chondrosarcoma in mice.
Authors: Calleja, Véronique, Henry, Jack C., Cobbaut, Mathias, Sewell, Joanne, Rizzoti, Karine, Houghton, Francesca, Boeing, Stefan, Anyanwu, Nneka, Varsani-Brown, Sunita, Snoeks, Thomas, Suárez-Bonnet, Alejandro, Priestnall, Simon L., McDonald, Neil Q., Cameron, Angus J. M., Parker, Peter J.
Source: Science Signaling; 11/4/2025, Vol. 18 Issue 911, p1-16, 16p
Subject Terms: BRAIN cancer, GAIN-of-function mutations, GENETIC mutation, TUMORS, CHONDROSARCOMA, KINASES, PROTEIN-protein interactions, EPIGENETICS
Abstract: The penetrant D463H mutation in PRKCA, which encodes the kinase PKCα, is a biomarker and driver of chordoid glioma, a type of brain cancer. Here, we found that heterozygous knock-in expression of the D463H mutant in mice elicited the development of chondrosarcomas. The mutant protein kinase was catalytically inactive, but no such oncogenic phenotype was observed for the related inactivating mutation D463N, indicating that the lack of activity per se was not the cause of the oncogenicity of the D463H mutant. In cultured glioma cells, the behavior of the D463H mutant closely mirrored that of wild-type PKCα and retained ATP binding, unlike the related D463N mutant. Mechanistically, PKCα D463H displayed quantitative alterations in its interactome compared with that of the wild-type kinase, with enhanced association with epigenetic regulators. This change in the interactome aligned with transcriptomic changes that resembled an increased PKCα-induced expression program, with enhanced gene signatures mediated by BRD4, MYC, and TGF-β. D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism. Editor's summary: Inactivating mutations in the kinase PKCα and loss of signaling output are associated with various cancers. Calleja et al. found that the D463H mutation that causes the brain cancer chordoid glioma inactivates its kinase activity but induces a gain-of-signal output through protein-protein interactions. D463H PKCα bound to ATP but lacked the ability to hydrolyze it, resulting in sustained interactions with effector proteins, an altered interactome, and enhanced gene expression programs. Heterozygous expression of the mutant in mice caused a rapid onset of bone cancer, demonstrating that the mutation confers dominant oncogenicity. The findings provide insights into PKCα function and may lead to strategies to treat the tumor in patients. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]
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Abstract:The penetrant D463H mutation in PRKCA, which encodes the kinase PKCα, is a biomarker and driver of chordoid glioma, a type of brain cancer. Here, we found that heterozygous knock-in expression of the D463H mutant in mice elicited the development of chondrosarcomas. The mutant protein kinase was catalytically inactive, but no such oncogenic phenotype was observed for the related inactivating mutation D463N, indicating that the lack of activity per se was not the cause of the oncogenicity of the D463H mutant. In cultured glioma cells, the behavior of the D463H mutant closely mirrored that of wild-type PKCα and retained ATP binding, unlike the related D463N mutant. Mechanistically, PKCα D463H displayed quantitative alterations in its interactome compared with that of the wild-type kinase, with enhanced association with epigenetic regulators. This change in the interactome aligned with transcriptomic changes that resembled an increased PKCα-induced expression program, with enhanced gene signatures mediated by BRD4, MYC, and TGF-β. D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism. Editor's summary: Inactivating mutations in the kinase PKCα and loss of signaling output are associated with various cancers. Calleja et al. found that the D463H mutation that causes the brain cancer chordoid glioma inactivates its kinase activity but induces a gain-of-signal output through protein-protein interactions. D463H PKCα bound to ATP but lacked the ability to hydrolyze it, resulting in sustained interactions with effector proteins, an altered interactome, and enhanced gene expression programs. Heterozygous expression of the mutant in mice caused a rapid onset of bone cancer, demonstrating that the mutation confers dominant oncogenicity. The findings provide insights into PKCα function and may lead to strategies to treat the tumor in patients. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]
ISSN:19450877
DOI:10.1126/scisignal.adr0235