TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-κB activation and tumor progression
TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-κB activation and tumor progression
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TMEM43/LUMA 是介导 EGFR 诱导的 NF-κB 激活和肿瘤进展的关键信号成分
DOI：
10.1038/onc.2016.430
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发表时间：
2017-05-18
期刊：
影响因子：
8
通讯作者：
Lin, X.
中科院分区：
文献类型：
--
作者：
Jiang, C.;Zhu, Y.;Lin, X.
表皮生长因子受体（EGFR）家族成员在细胞增殖、分化和存活中起关键作用。EGFR的过表达和突变或异常EGFR信号传导通常与各种癌症的发展相关，其中通常发现组成型NF-κB活化促进参与癌细胞增殖、存活、迁移和上皮-间充质转化的各种蛋白质的表达。然而，EGFR诱导NF-κB活化的机制尚未完全确定。本研究采用基于双分子荧光互补的功能基因组学方法进行高通量筛选，确定TMEM 43/LUMA是EGFR信号网络中的关键组分，介导EGFR诱导的NF-κB活化。我们的数据显示，EGFR在EGF刺激后招募TMEM 43。TMEM 43与支架蛋白CARMA 3及其缔合复合物相互作用以诱导下游NF-κB活化，并且在控制细胞存活中起关键作用。TMEM 43缺陷显著影响集落形成、失巢凋亡诱导的细胞死亡的存活、体外癌细胞的迁移和侵袭以及体内肿瘤进展。重要的是，TMEM 43的高表达与脑肿瘤恶性程度密切相关，抑制脑肿瘤细胞中的TMEM 43表达可抑制其体外和体内生长。总之，我们的研究揭示了EGF受体与NF-κB活化和肿瘤进展的关键联系。
Epidermal growth factor receptor (EGFR) family members play pivotal roles in cell proliferation, differentiation and survival. Overexpression and mutations of EGFRs, or aberrant EGFR signaling are commonly associated with the development of various cancers, where constitutive NF-κB activation is often found to promote the expression of various proteins involved in the proliferation, survival, migration and epithelial-to-mesenchymal transition of cancer cells. However, the mechanism of EGFR-induced NF-κB activation is not fully defined. Here, we used a Bimolecular Fluorescence Complementation-based functional genomics method to perform a high throughput screening and identified TMEM43/LUMA as a critical component in EGFR signaling network, mediating EGFR-induced NF-κB activation. Our data show that EGFR recruits TMEM43 following EGF stimulation. TMEM43 interacts with the scaffold protein CARMA3 and its associating complex to induce downstream NF-κB activation, and plays a critical role in controlling cell survival. TMEM43 deficiency significantly affects colony formation, survival of anoikis-induced cell death, migration and invasion of cancer cells in vitro, as well as tumor progression in vivo. Importantly, higher expression of TMEM43 closely correlates with brain tumor malignancy, and suppression of TMEM43 expression in brain tumor cells inhibited their growth both in vitro and in vivo. Altogether, our studies reveal a crucial link of EGF receptor to NF-κB activation and tumor progression.