CARMA3 is crucial for EGFR-Induced activation of NF-κB and tumor progression

Cancer Res. 2011 Mar 15;71(6):2183-92. doi: 10.1158/0008-5472.CAN-10-3626.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / metabolism*
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • I-kappa B Proteins / metabolism
  • Male
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Nude
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • RNA Interference
  • Transplantation, Heterologous
  • Tumor Burden

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • CARD Signaling Adaptor Proteins
  • CARD10 protein, human
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • NF-KappaB Inhibitor alpha
  • Epidermal Growth Factor
  • ErbB Receptors