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Clustering of CARMA1 through SH3–GUK domain interactions is required for its activation of NF-κB signalling

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  • Hiromitsu Hara

    (Faculty of Medicine, Saga University
    Graduate School of Medical and Dental Sciences, Kagoshima University)

  • Tadashi Yokosuka

    (Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences
    PRESTO, Japan Science and Technology Agency)

  • Hideki Hirakawa

    (Laboratory of Plant Genome Informatics, Kazusa DNA Research Institute)

  • Chitose Ishihara

    (PRESTO, Japan Science and Technology Agency)

  • Shinsuke Yasukawa

    (Graduate School of Medical Sciences, Kyushu University)

  • Masanori Yamazaki

    (Faculty of Medicine, Saga University)

  • Haruhiko Koseki

    (Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences)

  • Hiroki Yoshida

    (Faculty of Medicine, Saga University)

  • Takashi Saito

    (Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences)

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.

Suggested Citation

  • Hiromitsu Hara & Tadashi Yokosuka & Hideki Hirakawa & Chitose Ishihara & Shinsuke Yasukawa & Masanori Yamazaki & Haruhiko Koseki & Hiroki Yoshida & Takashi Saito, 2015. "Clustering of CARMA1 through SH3–GUK domain interactions is required for its activation of NF-κB signalling," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
  • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms6555
    DOI: 10.1038/ncomms6555
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