This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shida, D. Articles by Nagawa, H. Search for Related Content PubMed PubMed Citation Articles by Shida, D. Articles by Nagawa, H.

Transactivation of Epidermal Growth Factor Receptor Is Involved in Leptin-Induced Activation of Janus-Activated Kinase 2 and Extracellular Signal–Regulated Kinase 1/2 in Human Gastric Cancer Cells

Department of Surgical Oncology, University of Tokyo Graduate School of Medicine, Tokyo, Japan

Requests for reprints: Dai Shida, Department of Surgical Oncology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-8653; Fax: 81-3-3811-6822; E-mail: dshida-tky{at}umin.ac.jp.

Leptin is known to act as a growth factor through the Janus-activated kinase (JAK)/signal transducer and activator of transcription signaling pathway as well as the mitogen-activated protein kinase pathway. In this study, we showed a novel signal transduction pathway using two human gastric cancer cell lines, MKN28 and MKN74. Both gastric cancer cells expressed leptin and its receptors (Ob-R) at the protein level. We found that leptin, even at as low as 0.1 ng/mL, induced significant tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Time-course experiments revealed that phosphorylation was maximal after 5 minutes of stimulation and declined thereafter. We also revealed that tyrosine phosphorylation of EGFR induced by leptin was significantly attenuated by two inhibitors, an EGFR tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of EGFR transactivation induced by leptin is dependent on proteolytically released EGFR ligands. Leptin induced JAK2 activation and extracellular signal–regulated kinase (ERK) 1/2 activation in these gastric cancer cells, both of which occurred after the peak of EGFR transactivation. Pretreatment of gastric cancer cells with AG1478 significantly reduced the degree of phosphorylation of both JAK2 and ERK1/2. These findings indicate the involvement of EGFR transactivation in the activation of JAK2 and ERK1/2. Our results reveal that EGFR transactivation is involved in the leptin signaling pathway in gastric cancer cells, which extends the physiologic action of leptin beyond its central effects in the hypothalamus to regulate body weight.

This article has been cited by other articles:

				L. Vona-Davis and D. P Rose Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression Endocr. Relat. Cancer, June 1, 2007; 14(2): 189 - 206. [Abstract] [Full Text] [PDF]

				O. Ogunwobi, G. Mutungi, and I. L. P. Beales Leptin Stimulates Proliferation and Inhibits Apoptosis in Barrett's Esophageal Adenocarcinoma Cells by Cyclooxygenase-2-Dependent, Prostaglandin-E2-Mediated Transactivation of the Epidermal Growth Factor Receptor and c-Jun NH2-Terminal Kinase Activation Endocrinology, September 1, 2006; 147(9): 4505 - 4516. [Abstract] [Full Text] [PDF]

				P. Ellmark, J. Ingvarsson, A. Carlsson, B. S. Lundin, C. Wingren, and C. A. K. Borrebaeck Identification of Protein Expression Signatures Associated with Helicobacter pylori Infection and Gastric Adenocarcinoma Using Recombinant Antibody Microarrays Mol. Cell. Proteomics, September 1, 2006; 5(9): 1638 - 1646. [Abstract] [Full Text] [PDF]