GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein
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
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
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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

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Figure 1

GRK2 binds to MALT1 and dissociates from MALT1 after AgR stimulation.

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GRK2 binds to MALT1 and dissociates from MALT1 after AgR stimulation. (A...
(A) Endogenous MALT1 and GRK2 interact in BJAB B and Jurkat T cells. Coimmunoprecipitation (co-IP) of MALT1 with GRK2 was demonstrated by Western blot. (B) Co-IP analysis reveals that purified recombinant GRK2 interacts directly with MALT1 (left) but not BCL10 (right). (C) AgR stimulation leads to GRK2/MALT1 dissociation in the same general time course as CARMA1 association with BCL10/MALT1. Jurkat T cells were serum-starved and exposed to PMA (50 ng/mL)/ionomycin (1 μM) (PMA/Iono) for the indicated times. Cell lysates were subjected to immunoprecipitation (IP) with anti-MALT1, followed by immunoblotting with either anti-GRK2, anti-CARMA1, or anti-BCL10. (D) Reverse immunoprecipitation with anti-GRK2 also confirmed that AgR stimulation leads to GRK2/MALT1 dissociation in Jurkat T cells. Cells were treated as in C, and cell lysates were subjected to immunoprecipitation with anti-GRK2, followed by immunoblotting with anti-MALT1. All blots shown are representative of 3 separate experiments.