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CARMA3 is Crucial for EGFR-Induced Activation of NF-κB and Tumor Progression

2011; American Association for Cancer Research; Volume: 71; Issue: 6 Linguagem: Inglês

10.1158/0008-5472.can-10-3626

1538-7445

Tang Jiang, Brian C. Grabiner, Yifan Zhu, Changying Jiang, Hongxiu Li, Yun You, Jing‐Yu Lang, Mien‐Chie Hung, Xin Lin,

Signaling Pathways in Disease

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.