Phosphorylation of TNF-α converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation

Qing Zhang, Sufi M. Thomas, Vivian Wai Yan Lui, Sichuan Xi, Jill M. Siegfried, Huizhou Fan, Thomas E. Smithgall, Gordon B. Mills, Jennifer Rubin Grandis

Research output: Contribution to journalArticle

113 Scopus citations

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-α 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.

Original languageEnglish (US)
Pages (from-to)6901-6906
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number18
DOIs
StatePublished - May 2 2006
Externally publishedYes

Keywords

  • G protein-coupled receptor
  • Squamous cell carcinoma of head and neck

ASJC Scopus subject areas

  • General

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