PXD049959 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | The penetrant chordoid glioma PRKCA mutation is a gain-of-function kinase inactivation eliciting early onset chondrosarcoma in mice |
Description | A highly penetrant heterozygous mutation in PRKCA was found recently in chordoid glioma. To establish whether this mutant of PKC was a driver of tumour formation or maintenance in vivo, knock-in mice were generated. The constitutive, heterozygous expression of the Prkca D463H mutant in mice provoked the development of bilateral hindlimb chondrosarcomas and early neonatal mortality. The lack of activity of the D463H mutant was not the trigger of the phenotype as heterozygous knock-in of the related inactivating mutation D463N produced offspring indistinguishable from parental strains. Moreover, this surprising distinction between D463H and D463N mutations did not reflect a selective lack of dominance for the D463N mutation over the wild type (WT) allele since homozygous expression of this mutation was phenotypically WT. In cell culture, the D463H mutant expression, localisation and downregulation behaviours closely mimicked that of the WT, with the D463N mutant displaying some subtle differences. Biochemically, both the D463H and D463N mutants were shown to be inactive, although based on thermal shift assays the D463N mutant had reduced ATP affinity compared to WT or D463H proteins. Using induced transcriptional changes as a functional readout, altered mRNA expression indicates that the D463H acts as a dominant gain-of-function PKC mutant, despite a complete lack of intrinsic kinase activity; transcriptional changes induced by the D463N mutant were distinct from both the WT and D463H mutant. These findings suggest a model in which there is a non-catalytic effector function of PKC which it is presumed operates through protein-protein interactions, as evidenced here by TurboID proximity labelling. The penetrant selection of the specific inactivating D463H mutation in chordoid glioma and the distinction with the D463N mutation indicates that this is conformationally sensitive. The properties characterised suggest this is driven by ATP binding and by inference, in this tissue context, the catalytic activity of this kinase acts as an autoregulatory negative feedback control. |
HostingRepository | PRIDE |
AnnounceDate | 2025-05-29 |
AnnouncementXML | Submission_2025-05-29_08:05:17.671.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | VERONIQUE CALLEJA |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | monohydroxylated residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-02-20 06:17:12 | ID requested | |
⏵ 1 | 2025-05-29 08:05:18 | announced | |
Publication List
Keyword List
submitter keyword: human,PKC alpha, glioma cell line |
Contact List
Peter Parker |
contact affiliation | Emeritus Group Leader Protein Phosphorylation Laboratory The Francis Crick Institute 1 Midland Road London NW1 1AT |
contact email | peter.parker@crick.ac.uk |
lab head | |
VERONIQUE CALLEJA |
contact affiliation | The Francis Crick Institute |
contact email | veronique.calleja@crick.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD049959
- Label: PRIDE project
- Name: The penetrant chordoid glioma PRKCA mutation is a gain-of-function kinase inactivation eliciting early onset chondrosarcoma in mice