Abstract
G protein-coupled receptors induce EGF receptor (EGFR) signaling, leading to the proliferation and invasion of cancer cells. Elucidation of the mechanism of EGFR activation by G protein-coupled receptors may identify new signaling paradigms. A gastrin-releasing peptide (GRP)/GRP receptor-mediated autocrine pathway was previously described in squamous cell carcinoma of head and neck. In the present study, we demonstrate that TNF-alpha converting enzyme (TACE), a disintegrin and metalloproteinse-17, undergoes a Src-dependent phosphorylation that regulates release of the EGFR ligand amphiregulin upon GRP treatment. Further investigation reveals the phosphatidylinositol 3-kinase (PI3-K) as the intermediate of c-Src and TACE, contributing to their association and TACE phosphorylation. Phosphoinositide-dependent kinase 1 (PDK1), a downstream target of PI3-K, has been identified as the previously undescribed kinase to directly phosphorylate TACE upon GRP treatment. These findings suggest a signaling cascade of GRP-Src-PI3-K-PDK1-TACE-amphiregulin-EGFR with multiple points of interaction, translocation, and phosphorylation. Furthermore, knockdown of PDK1 augmented the antitumor effects of the EGFR inhibitor erlotinib, indicating PDK1 as a therapeutic target to improve the clinical response to EGFR inhibitors.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAM17 Protein
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Amphiregulin
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Antineoplastic Agents / metabolism
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CSK Tyrosine-Protein Kinase
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Cell Line
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EGF Family of Proteins
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Erlotinib Hydrochloride
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Gastrin-Releasing Peptide / genetics
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Gastrin-Releasing Peptide / metabolism*
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Glycoproteins / genetics
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Glycoproteins / metabolism*
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Protein Kinase Inhibitors / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Quinazolines / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology*
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Tumor Necrosis Factor-alpha / metabolism
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src-Family Kinases
Substances
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AREG protein, human
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Amphiregulin
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Antineoplastic Agents
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EGF Family of Proteins
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Glycoproteins
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Intercellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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Quinazolines
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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Gastrin-Releasing Peptide
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Erlotinib Hydrochloride
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ErbB Receptors
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Protein-Tyrosine Kinases
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human
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3-Phosphoinositide-Dependent Protein Kinases
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PDPK1 protein, human
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Protein Serine-Threonine Kinases
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ADAM Proteins
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ADAM17 Protein
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ADAM17 protein, human