Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
BRET(n)
cancer genomics
cancer target
driver mutations
interactome
neoPPI
oncogene
protein-protein interaction
systems biology
tumor suppressor
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
26 05 2022
26 05 2022
Historique:
received:
06
09
2021
revised:
27
02
2022
accepted:
08
04
2022
pubmed:
6
5
2022
medline:
1
6
2022
entrez:
5
5
2022
Statut:
ppublish
Résumé
Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAF
Identifiants
pubmed: 35512704
pii: S0092-8674(22)00461-5
doi: 10.1016/j.cell.2022.04.014
pmc: PMC9597701
mid: NIHMS1802312
pii:
doi:
Substances chimiques
Kelch-Like ECH-Associated Protein 1
0
NF-E2-Related Factor 2
0
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1974-1985.e12Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM008602
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA217691
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA138292
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002378
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217842
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217875
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests H.F. is scientific founder of PiVista Therapeutics.
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