Phosphorylation of TNF-alpha Converting Enzyme by Gastrin-releasing Peptide Induces Amphiregulin Release and EGF Receptor Activation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Apr 28

PMID 16641105

Citations 75

Authors

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

Affiliations

Soon will be listed here.

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.

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