Hepatocyte Growth Factor Induces Epithelial Cell Motility Through Transactivation of the Epidermal Growth Factor Receptor

Abstract

Purpose:: Hepatocyte growth factor (HGF) is a potent inducer of motility in epithelia. It is produced by the corneal stroma, whereas its receptor, MET, is present in the corneal epithelium. In penetrating wounds, HGF comes into contact with MET thereby promoting cell migration. Activation of the epidermal growth factor receptor (EGFR) is critical for wound-induced cell migration, and we therefore asked whether activation of the EGFR is important for induction of motility by HGF.

Methods:: Motility was monitored by healing of wounds in sheets of an immortalized line of corneal epithelial cells, and by scattering of colonies of the cells. Activation of the EGFR was measured by immunoblotting with an antibody that recognizes tyr-1173. Tyrphostin AG 1478 and several neutralizing antibodies were used to block EGFR activation.

Results:: HGF induces transactivation of the epidermal growth factor receptor (EGFR) in corneal epithelial cells, and EGFR activation is absolutely required for induction of motility in these cells. Activation of the EGFR occurs through amphiregulin and the heparin-binding epidermal growth factor-like growth factor. Blocking EGFR activation does not inhibit ERK1/2 activation by HGF, and EGF only partially induces a motile phenotype in the corneal epithelial cells. Transactivation of the EGFR was also observed in skin keratinocytes and in MDCK cells.

Conclusions:: HGF transactivates the EGFR in corneal epithelial cells, and activation of the EGFR is necessary although not sufficient to induce full motility by HGF. Abnormal HGF/MET signaling is a common cause of invasive and metastatic properties of human cancers, and our findings suggest that the EGFR is a relevant therapeutic target in such tumors.

Keywords: growth factors/growth factor receptors • wound healing • cornea: basic science