HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science 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 Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Xu, K.-P. Articles by Yu, F.-S. X. Search for Related Content PubMed PubMed Citation Articles by Xu, K.-P. Articles by Yu, F.-S. X.

Cross Talk between c-Met and Epidermal Growth Factor Receptor during Retinal Pigment Epithelial Wound Healing

From the Kresge Eye Institute, Departments of Ophthalmology and of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan.

PURPOSE. The authors sought to determine how hepatocyte growth factor (HGF) receptor c-Met and epidermal growth factor receptor (EGFR) cross talk in response to injury in human ARPE-19 cells.

METHODS. A scratch wound was made on a cell monolayer of ARPE-19 cells using a sequence-comb or a pipet tip, and it was allowed to heal in the presence or absence of HGF and heparin-binding EGF-like growth factor (HB-EGF). The activation of EGFR was analyzed by immunoprecipitation with EGFR antibody, followed by Western blotting with phosphotyrosine-specific antibody. Phosphorylation of extracellular signal-regulated kinase (ERK) and AKT (a major substrate of phosphatidylinositol 3'-kinase (PI3K) was assessed by Western blotting. The release of c-Met ectodomain into the culture media was determined by Western blotting using an antibody against the extracellular region. Cell migration was assessed by Boyden chamber migration assay.

RESULTS. ARPE-19 cells underwent spontaneous wound healing in basal medium, and exogenously added HB-EGF and HGF significantly enhanced wound closure. Basal and growth factor-enhanced wound closures were attenuated but not slowed by hydroxyurea, a cell proliferation inhibitor. RPE cells expressed all four erbBs, and wounding induced EGFR transactivation and downstream ERK and PI3K phosphorylation in ARPE-19 cells. HGF also induced EGFR tyrosine phosphorylation. The EGFR kinase inhibitor AG1478 blocked wound- and HGF-stimulated EGFR transactivation and attenuated spontaneous and growth factor-induced wound closure. Wounding and EGFR ligands induced the release of c-Met into the culture media. Moreover, pretreatment of cells with HB-EGF impaired ARPE-19 migration toward HGF in a matrix metalloproteinase inhibitor-sensitive manner.

CONCLUSIONS. EGFR modulates HGF/c-Met activity by inducing c-Met ectodomain shedding, and HGF/c-Met transactivates EGFR, leading to an enhanced activation of downstream signaling pathways. Cross talk between EGFR and c-Met may play a key role in regulating RPE cell migration, proliferation, and wound healing.

This article has been cited by other articles:

				L. P. Desai, S. R. White, and C. M. Waters Cyclic Mechanical Stretch Decreases Cell Migration by Inhibiting Phosphatidylinositol 3-Kinase- and Focal Adhesion Kinase-mediated JNK1 Activation J. Biol. Chem., February 12, 2010; 285(7): 4511 - 4519. [Abstract] [Full Text] [PDF]

				P. Accornero, S. Miretti, L. Starvaggi Cucuzza, E. Martignani, and M. Baratta Epidermal growth factor and hepatocyte growth factor cooperate to enhance cell proliferation, scatter, and invasion in murine mammary epithelial cells J. Mol. Endocrinol., February 1, 2010; 44(2): 115 - 125. [Abstract] [Full Text] [PDF]

				J. K. Rho, Y. J. Choi, J. K. Lee, B.-Y. Ryoo, I. I. Na, S. H. Yang, S. S. Lee, C. H. Kim, Y. D. Yoo, and J. C. Lee The Role of MET Activation in Determining the Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Mol. Cancer Res., October 1, 2009; 7(10): 1736 - 1743. [Abstract] [Full Text] [PDF]

				P. Accornero, E. Martignani, S. Miretti, L. Starvaggi Cucuzza, and M. Baratta Epidermal growth factor and hepatocyte growth factor receptors collaborate to induce multiple biological responses in bovine mammary epithelial cells J Dairy Sci, August 1, 2009; 92(8): 3667 - 3675. [Abstract] [Full Text] [PDF]

				B. J. Ryckman, M. C. Chase, and D. C. Johnson HCMV gH/gL/UL128-131 interferes with virus entry into epithelial cells: Evidence for cell type-specific receptors PNAS, September 16, 2008; 105(37): 14118 - 14123. [Abstract] [Full Text] [PDF]

				M. A. Hallman, S. Zhuang, and R. G. Schnellmann Regulation of Dedifferentiation and Redifferentiation in Renal Proximal Tubular Cells by the Epidermal Growth Factor Receptor J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 520 - 528. [Abstract] [Full Text] [PDF]