GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein
Jing Cheng, … , Peter C. Lucas, Linda M. McAllister-Lucas
Jing Cheng, … , Peter C. Lucas, Linda M. McAllister-Lucas
Published January 21, 2020
Citation Information: J Clin Invest. 2020;130(2):1036-1051. https://doi.org/10.1172/JCI97040.
View: Text | PDF
Research Article Immunology Oncology

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

×

Figure 2

GRK2 N-terminus binds to MALT1 death domain and inhibits MALT1-dependent NF-κB activation.

Options: View larger image (or click on image) Download as PowerPoint
GRK2 N-terminus binds to MALT1 death domain and inhibits MALT1-dependent...
(A) GRK2 binds to the MALT1 death domain (DD). Co-IP of HA-tagged MALT1 constructs with endogenous GRK2 in HEK293T cells is shown (left). Blot is representative of 3 independent experiments. Schematic of domain structures of full-length (FL) MALT1 and deletion mutants is shown at right. (B) Both WT and kinase-deficient (K220R) GRK2 inhibit BCL10/MALT1–induced NF-κB luciferase reporter activity (left). Lanes were run on the same gel and were noncontiguous in the leftmost blot; the vertical dividing line shows where images are spliced together. GRK2 does not affect API2-MALT1–induced (middle) or p76 MALT1–induced (right) NF-κB luciferase reporter activity (n = 3). (C) GRK2 αN/RH (aa 1–173) interacts with endogenous MALT1. Proteins were expressed in HEK293T cells, and co-IP was assessed by Western blot (left). Blot is representative of 3 independent experiments. Domain structures of full-length GRK2 and deletion mutants are shown at right. (D) The GRK2 αN/RH fragment (aa 1–173) inhibits BCL10/MALT1–induced NF-κB luciferase reporter activity in a dose-dependent manner (n = 3). All values are represented as mean ± SEM. **P < 0.01, ***P < 0.001, by 1-way ANOVA, followed by Tukey’s multiple-comparisons test.