GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.

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State: Public
Version: Final published version
License: Not specified
Serval ID
serval:BIB_FFB7B759EC40
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.
Journal
The Journal of clinical investigation
Author(s)
Cheng J., Klei L.R., Hubel N.E., Zhang M., Schairer R., Maurer L.M., Klei H.B., Kang H., Concel V.J., Delekta P.C., Dang E.V., Mintz M.A., Baens M., Cyster J.G., Parameswaran N., Thome M., Lucas P.C., McAllister-Lucas L.M.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Publication state
Published
Issued date
03/02/2020
Peer-reviewed
Oui
Volume
130
Number
2
Pages
1036-1051
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
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.
Keywords
Immunology, Lymphomas, NF-kappaB, Oncology, Signal transduction
Pubmed
Open Access
Yes
Create date
23/01/2020 16:11
Last modification date
29/04/2020 6:20
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