期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms6555
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [21390153]
- Takeda Science Foundation
- Naito Foundation
- Tokyo Biochemical Research Foundation
- Sagawa Foundation for Promotion of Cancer Research
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Grants-in-Aid for Scientific Research [21390153, 25460594, 25113725, 24390256] Funding Source: KAKEN
CARMA1-mediated NF-kappa B 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-kappa B activation. However, regulatory mechanisms and relevance of CARMA1 clusters in the NF-kappa B 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-kappa B 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.
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