GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein.

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.

• Authors: Jing Cheng, Linda R Klei, Nathaniel E Hubel, Ming Zhang, Rebekka Schairer, Lisa M Maurer, Hanna B Klei, Heejae Kang, Vincent J Concel, Phillip C Delekta, Eric V Dang, Michelle A Mintz, Mathijs Baens, Jason G Cyster, Narayanan Parameswaran, Margot Thome, Peter C Lucas, Linda M McAllister-Lucas
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 2 Pg. 1036-1051 (02 03 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 31961340 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Oncogene Proteins
• GRK2 protein, human
• G-Protein-Coupled Receptor Kinase 2
• MALT1 protein, human
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein

Topics

• Animals
• Carcinogenesis (genetics, metabolism, pathology)
• Female
• G-Protein-Coupled Receptor Kinase 2 (genetics, metabolism)
• Humans
• Jurkat Cells
• Lymphoma, Large B-Cell, Diffuse (genetics, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein (genetics, metabolism)
• Oncogene Proteins (genetics, metabolism)