期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 2, 页码 1036-1051出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI97040
关键词
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资金
- Conover family
- Swiss National Science Foundation
- Swiss Cancer League
- Emma Muschamp Foundation
- University of Pittsburgh Physicians Foundation
- NIH [R01 CA124540]
- University of Pittsburgh Hillman Cancer Center Support Grant [5P30 CA047904]
- UPMC Hillman Cancer Center
Antigen receptor-dependent (AgR-dependent) stimulation of the NF-KB 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-kappa B machinery and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-kappa B. 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.
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