Abstract
CARMA1-mediated NF-κB activation controls lymphocyte activation through antigen receptors and survival of some malignant lymphomas. CARMA1 clusters are formed on physiological receptor-mediated activation or by its oncogenic mutation in activated B-cell-diffuse large B-cell lymphomas (ABC-DLBCLs) with constitutive NF-κB activation. However, regulatory mechanisms and relevance of CARMA1 clusters in the NF-κB pathway are unclear. Here we show that SH3 and GUK domain interactions of CARMA1 link CARMA1 clustering to signal activation. SH3 and GUK domains of CARMA1 interact by either intra- or intermolecular mechanisms, which are required for activation-induced assembly of CARMA1. Disruption of these interactions abolishes the formation of CARMA1 microclusters at the immunological synapse, CARMA-regulated signal activation following antigen receptor stimulation as well as spontaneous CARMA1 clustering and NF-κB activation by the oncogenic CARMA1 mutation in ABC-DLBCLs. Thus, the SH3-GUK interactions that regulate CARMA1 cluster formations are promising therapeutic targets for ABC-DLBCLs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CARD Signaling Adaptor Proteins / biosynthesis*
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CARD Signaling Adaptor Proteins / chemistry
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Cluster Analysis
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Crystallography, X-Ray
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Disks Large Homolog 4 Protein
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Female
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Guanylate Cyclase / biosynthesis*
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Guanylate Cyclase / chemistry
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Guanylate Kinases / biosynthesis
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Guanylate Kinases / chemistry
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Humans
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Immune System / physiology
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Intracellular Signaling Peptides and Proteins / biosynthesis
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Intracellular Signaling Peptides and Proteins / chemistry
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Jurkat Cells
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Lymphocytes / cytology
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Male
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Membrane Proteins / biosynthesis
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Membrane Proteins / chemistry
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microscopy, Fluorescence
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Mutation
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NF-kappa B p50 Subunit / metabolism*
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Protein Binding
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Protein Conformation
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Protein Structure, Tertiary
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Rats
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Signal Transduction*
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Subcellular Fractions / metabolism
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src Homology Domains
Substances
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CARD Signaling Adaptor Proteins
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Card11 protein, mouse
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DLG4 protein, human
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Dlg4 protein, rat
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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NF-kappa B p50 Subunit
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NFKB1 protein, human
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Nfkb1 protein, mouse
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Guanylate Kinases
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CARD11 protein, human
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Guanylate Cyclase