GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.
Détails
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Accès restreint UNIL
Etat: Public
Version: Final published version
Licence: Non spécifiée
Accès restreint UNIL
Etat: Public
Version: Final published version
Licence: Non spécifiée
ID Serval
serval:BIB_FFB7B759EC40
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.
Périodique
The Journal of clinical investigation
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Statut éditorial
Publié
Date de publication
03/02/2020
Peer-reviewed
Oui
Volume
130
Numéro
2
Pages
1036-1051
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
Antigen receptor-dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein-coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.
Mots-clé
Immunology, Lymphomas, NF-kappaB, Oncology, Signal transduction
Pubmed
Open Access
Oui
Création de la notice
23/01/2020 15:11
Dernière modification de la notice
29/04/2020 5:20