We demonstrated that proteoglycan is required for hepatocyte growth factor/scatter factor (HGF/SF) cross-linking to Met and sustained signal transduction. The amino-terminal domain of HGF/SF is responsible both for heparin-binding and ligand oligomerization; the latter is markedly enhanced by proteoglycan. A number of cell lines with varying phenotypes have been established from HGF/SF transgenic mouse liver. Preliminary trans-plantation experiments have been performed to study the capacity of these cells to differentiate into distinct cellular phenotypes during hepatocyte regeneration. Extending earlier observations of its cytoprotective effects, exogenous administration of keratinocyte growth factor (KGF or FGF 7) was shown to block apoptosis in an experimental model developed in the mouse uterus. Similar results have been obtained in rhesus monkey, where stabilization and perhaps hypertrophy of spiral arteries also was noted, despite the withdrawal of progesterone. Our studies of the KGF-binding frizzled-related protein (FRP) have established that it binds hyaluronic acid as well as heparin. In situ hybridization and immunohistochemical analysis have been initiated to determine the expression of this gene in whole tissue. Initial collaborative experiments suggest that FRP can function as an inhibitor of Wnt signaling, consistent with the recent discovery that frizzled proteins are receptors for members of the Wnt family of molecules.
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