Cheng J, Klei LR, Hubel NE, Zhang M, Schairer R, Maurer LM, Klei HB, Kang H, Concel VJ, Delekta PC, Dang EV, Mintz MA, Baens M, Cyster JG, Parameswaran N, Thome M, Lucas PC, McAllister-Lucas LM. GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein. J Clin Invest. 2020 Jan 21. pii: 97040. doi: 10.1172/JCI97040. [Epub ahead of print] PubMed PMID: 31961340.
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.
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