The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells.

K M Weidner,M Sachs,W Birchmeier

doi:10.1083/jcb.121.1.145

Abstract

Depending on the target cells and culture conditions, scatter factor/hepatocyte growth factor (SF/HGF) mediates several distinct activities, i.e., cell motility, proliferation, invasiveness, tubular morphogenesis, angiogenesis, or cytotoxicity. A small isoform of SF/HGF encoded by a natural splice variant, which consists of the NH2-terminal hairpin structure and the first two kringle domains but not the protease homology region, induces cell motility but not mitogenesis. Two types of SF/HGF receptors have recently been discovered in epithelial cells, the high affinity c-Met receptor tyrosine kinase, and low affinity/high capacity binding sites, which are probably located on heparan sulfate proteoglycans. In the present study, we have addressed the question whether the various biological activities of SF/HGF are transduced into cells by a single type of receptor. We have here examined MDCK epithelial cells transfected with a hybrid cDNA encoding the ligand binding domain of the nerve growth factor (NGF) receptor and the membrane-spanning and tyrosine kinase domains of the Met receptor. We demonstrate that all biological effects of SF/HGF upon epithelial cells such as the induction of cell motility, proliferation, invasiveness, and tubular morphogenesis can now be triggered by the addition of NGF. Thus, it is likely that all known biological signals of SF/HGF are transduced through the receptor tyrosine kinase encoded by the c-Met protooncogene.

Highlights

Depending on the target cells and culture conditions, scatter factor/hepatocyte growth factor (SF/HGF) mediates several distinct activities, i.e., cell motility, proliferation, invasiveness, tubular morphogenesis, angiogenesis, or cytotoxicity
S CATTER factor/hepatocyte growth factor (SF/HGF) ~ has several distinct effects on cells in culture: (a) it is a strong mitogen for primary hepatocytes as well as other cell lines (Nakamura et al, 1987; Gohda et al, 1988; Zarnegar and Michalopoulos, 1989; Rubin et al, 1991); (b) it was independently identified as a motility and invasioninducing factor for epithelial and endothelial cells (Stoker et al, 1987; Gherardi et al, 1989; Rosen et al, 1990; Weidner et al, 1990, 1991; Bussolino et al, 1992); (c) it has cytotoxic and cytostatic effects on certain other cell lines (Higashio et al, 1990; Tajima et al, 1991; Shiota et al, 1992); and (d) it was found to be an inducer of epithelial tubulogenesis (Montesano et al, 1991a,b)
We have introduced into epithelial cells a eDNA expression vector encoding a hybrid tyrosine kinase receptor which consists of the membrane spanning and cytoplasmic domains of Met fused to the extracellular domain of the nerve growth factor (NGF) receptor

Summary

Introduction

Depending on the target cells and culture conditions, scatter factor/hepatocyte growth factor (SF/HGF) mediates several distinct activities, i.e., cell motility, proliferation, invasiveness, tubular morphogenesis, angiogenesis, or cytotoxicity. Two types of SF/HGF receptors have recently been discovered in epithelial cells, the high affinity c-Met receptor tyrosine kinase, and low affinity/high capacity binding sites, which are probably located on heparan sulfate proteoglycans. We demonstrate that all biological effects of SF/HGF upon epithelial cells such as the induction of cell motility, proliferation, invasiveness, and tubular morphogenesis can be triggered by the addition of NGE it is likely that all known biological signals of SF/HGF are transduced through the receptor tyrosine kinase encoded by the c-Met protooncogene. The a-chain and the NH2-terminal portion of the/~-chain are exposed on the cell surface, the COOH-terminal portion of the/~-chain is located in the cytoplasm and contains the tyrosine kinase domainand phosphorylation sites involved in the regulation of

Methods

Results

Conclusion