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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.

Citation

Hiromitsu Hara, Tadashi Yokosuka, Hideki Hirakawa, Chitose Ishihara, Shinsuke Yasukawa, Masanori Yamazaki, Haruhiko Koseki, Hiroki Yoshida, Takashi Saito. Clustering of CARMA1 through SH3-GUK domain interactions is required for its activation of NF-κB signalling. Nature communications. 2015;6:5555

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PMID: 25602919

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