title: Phosphorylation of TNF-alpha converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation.
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.
authors.affiliation: Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Sufi M
authors.initials: SM
authors.lastname: Thomas
authors.forename: Vivian Wai Yan
authors.initials: VW
authors.lastname: Lui
authors.forename: Sichuan
authors.initials: S
authors.lastname: Xi
authors.forename: Jill M
authors.initials: JM
authors.lastname: Siegfried
authors.forename: Huizhou
authors.initials: H
authors.lastname: Fan
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Smithgall
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Jennifer Rubin
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D066258:Amphiregulin; D000970:Antineoplastic Agents / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D019886:Gastrin-Releasing Peptide / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019061:src-Family Kinases
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D066258:Amphiregulin; D000970:Antineoplastic Agents; D000081247:CSK Tyrosine-Protein Kinase; D066255:EGF Family of Proteins; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D019886:Gastrin-Releasing Peptide; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases; C587848:AREG protein, human; C000631346:CSK protein, human; C578562:PDPK1 protein, human; C000606462:ADAM17 protein, human