Cell Growth & Differentiation, Vol 5, Issue 4 359-366, Copyright © 1994 by American Association of Cancer Research

ARTICLES

Receptor chimeras indicate that the met tyrosine kinase mediates the motility and morphogenic responses of hepatocyte growth/scatter factor

H Zhu, MA Naujokas and M Park
Molecular Oncology Group, Royal Victoria Hospital, Montreal, Quebec, Canada.

The met protooncogene is a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF is a multifunctional cytokine secreted mainly by mesenchymal cells that stimulates movement, invasion, and morphogenesis of some epithelial and endothelial cells and mitogenicity of others. Although the met receptor tyrosine kinase is a high affinity receptor for HGF/SF, it is not known whether this receptor can mediate the pleiotropic functions of HGF/SF. To investigate this in epithelial cells that normally respond to HGF/SF, we generated a chimeric receptor containing the extracellular domain from the colony stimulating factor 1 (CSF-1) receptor fused to the transmembrane and cytoplasmic domain of the met receptor. We show that the CSF-MET chimera, when expressed in Madin-Darby canine kidney (MDCK) epithelial cells, is fully functional. Treatment of MDCK cells expressing the chimera with CSF-1 leads to cell dissociation and scattering, as well as invasion and tubule formation of cells grown in collagen matrices. This effect is dependent on a functional met kinase. Stimulation of the receptor chimera with CSF-1 leads to activation of the met kinase and tyrosine phosphorylation of the chimeras in vivo, whereas a kinase inactive mutant chimera shows no biological response to CSF-1. These findings demonstrate that stimulation of the met kinase is sufficient and essential to mediate the motogenic, invasive, and morphogenic responses of MDCK cells to HGF/SF and that this is a suitable system for a detailed analysis of the molecular signaling events involved in these responses.

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