title: EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells.
abstract: Activation of nuclear factor κB (NFκB) is a central event in the responses of normal cells to inflammatory signals, and the abnormal constitutive activation of NFκB is important for the survival of most cancer cells. In nonmalignant human cells, EGF stimulates robust activation of NFκB. The kinase activity of the EGF receptor (EGFR) is required, because the potent and specific inhibitor erlotinib blocks the response. Down-regulating EGFR expression or inhibiting EGFR with erlotinib impairs constitutive NFκB activation in several different types of cancer cells and, conversely, increased activation of NFκB leads to erlotinib resistance in these cells. We conclude that EGF is an important mediator of NFκB activation in cancer cells. To explore the mechanism, we selected an erlotinib-resistant cell line in which the guanine nucleotide exchange factor Son of Sevenless 1 (SOS1), well known to be important for EGF-dependent signaling to MAP kinases, is overexpressed. Increased expression of SOS1 increases NFκB activation in several different types of cancer cells, and ablation of SOS1 inhibits EGF-induced NFκB activation in these cells, indicating that SOS1 is a functional component of the pathway connecting EGFR to NFκB activation. Importantly, the guanine nucleotide exchange activity of SOS1 is not required for NFκB activation.
authors: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors: Sarmishtha
authors: S
authors: De
authors: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors: Josephine Kam Tai
authors: JK
authors: Dermawan
authors: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 starkg@ccf.org.
authors: George R
authors: GR
authors: Stark
mesh_terms: D001940:Breast / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020837:SOS1 Protein; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors