CARMA3 is crucial for EGFR-Induced activation of NF-κB and tumor progression.
CARMA3 is crucial for EGFR-Induced activation of NF-κB and tumor progression.
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DOI：
10.1158/0008-5472.can-10-3626
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Jiang T;Grabiner B;Zhu Y;Jiang C;Li H;You Y;Lang J;Hung MC;Lin X
EGF激活NF-κB，组成性激活的NF-κB促进EGFR突变相关的肿瘤发生，但EGFR信号传导如何导致NF-κB激活仍不清楚。在这里，我们报告CARMA 3，一种含有半胱天冬酶募集结构域（CARD）的支架分子，是EGF诱导的NF-κB活化所必需的。CARMA 3缺陷损害EGF刺激后IKK复合物的活化，导致EGF诱导的IκBα磷酸化和NF-κB活化缺陷。我们发现CARMA 3和Bcl 10与EGFR相关恶性肿瘤的几个特征有关，包括增殖、存活、迁移和侵袭。最重要的是，CARMA 3有助于体内肿瘤生长。我们的研究结果阐明了EGFR近端信号成分和下游IKK复合物之间的关键联系，并为EGFR驱动的癌症的治疗提供了新的治疗靶点。
EGF activates NF-κB and constitutively activated NF-κB contributes to EGFR mutation-associated tumorigenesis, but it remains unclear precisely how EGFR signaling leads to NF-κB activation. Here we report that CARMA3, a Caspase Recruitment Domain (CARD)-containing scaffold molecule, is required for EGF-induced NF-κB activation. CARMA3 deficiency impaired the activation of the IKK complex following EGF stimulation, resulting in a defect of EGF-induced IκBα phosphorylation and NF-κB activation. We found that CARMA3 and Bcl10 contributed to several characteristics of EGFR-associated malignancy, including proliferation, survival, migration, and invasion. Most importantly, CARMA3 contributed to tumor growth in vivo. Our findings elucidate a crucial link between EGFR-proximal signaling components and the downstream IKK complex, and they suggest a new therapeutic target for treatment of EGFR-driven cancers.