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- Publisher Website: 10.1073/pnas.0509719103
- Scopus: eid_2-s2.0-33646468634
- PMID: 16641105
- WOS: WOS:000237399900023
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Article: Phosphorylation of TNF-α converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation
Title | Phosphorylation of TNF-α converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation |
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Authors | |
Keywords | G protein-coupled receptor Squamous cell carcinoma of head and neck |
Issue Date | 2006 |
Citation | Proceedings of the National Academy of Sciences of the United States of America, 2006, v. 103 n. 18, p. 6901-6906 How to Cite? |
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. © 2006 by The National Academy of Sciences of the USA. |
Persistent Identifier | http://hdl.handle.net/10722/194160 |
ISSN | 2021 Impact Factor: 12.779 2020 SCImago Journal Rankings: 5.011 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Zhang, Q | - |
dc.contributor.author | Thomas, SM | - |
dc.contributor.author | Lui, VWY | - |
dc.contributor.author | Xi, S | - |
dc.contributor.author | Siegfried, JM | - |
dc.contributor.author | Fan, H | - |
dc.contributor.author | Smithgall, TE | - |
dc.contributor.author | Mills, GB | - |
dc.contributor.author | Grandis, JR | - |
dc.date.accessioned | 2014-01-30T03:32:14Z | - |
dc.date.available | 2014-01-30T03:32:14Z | - |
dc.date.issued | 2006 | - |
dc.identifier.citation | Proceedings of the National Academy of Sciences of the United States of America, 2006, v. 103 n. 18, p. 6901-6906 | - |
dc.identifier.issn | 0027-8424 | - |
dc.identifier.uri | http://hdl.handle.net/10722/194160 | - |
dc.description.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. © 2006 by The National Academy of Sciences of the USA. | - |
dc.language | eng | - |
dc.relation.ispartof | Proceedings of the National Academy of Sciences of the United States of America | - |
dc.subject | G protein-coupled receptor | - |
dc.subject | Squamous cell carcinoma of head and neck | - |
dc.title | Phosphorylation of TNF-α converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1073/pnas.0509719103 | - |
dc.identifier.pmid | 16641105 | - |
dc.identifier.scopus | eid_2-s2.0-33646468634 | - |
dc.identifier.volume | 103 | - |
dc.identifier.issue | 18 | - |
dc.identifier.spage | 6901 | - |
dc.identifier.epage | 6906 | - |
dc.identifier.isi | WOS:000237399900023 | - |
dc.identifier.f1000 | 1033446 | - |
dc.identifier.issnl | 0027-8424 | - |