Three hepatocyte growth factor (HGF) isoforms encoded by alternatively spliced mRNA transcripts: have been identified and characterized: full- length HGF and two C-terminally-truncated forms designated HGF/NK2 and HGF/NK1. Both smaller isoforms compete for full-length HGF for receptor binding, but have diminished or undetectable mitogenic activity. All three isoforms are able to stimulate epithelial cell scattering and activate receptor- kinase autophosphorylation. There are differences, however, in the pattern of activation of cytoplasmic molecules that constitute the signaling cascade common to several growth factors, cytokines and environmental insults. A comparison of the effects of HGF, HGF/NK2 and HGF/NK1 binding on: (1) the sites of HGF receptor autophosphorylation, (2) the formation of receptor dimers and/or oligomers, (3) the activation of putative second messenger molecules, (4) the intracellular fate of ligand-receptor complexes and (5) the phosphorylation of unidentified intracellular molecules is in progress. The role of heparin-like proteoglycan in the binding and activation of the KGF receptor has been characterized. These studies include the identification of heparin-like proteoglycan binding sites on both KGF and its receptor, estimation of the dissociation constants for these interactions and the reconstitution of ligand-receptor interactions in model proteoglycan/extracellular- matrix environments. These studies indicate that although heparin- proteoglycan has long been considered an inhibitor of KGF/KGF-receptor interactions, it is essential for KGF binding and receptor activation. However, unlike other fibroblast growth factor family members, KGF can be inhibited by soluble heparin above a specific threshold concentration. Naturally occurring cellular environments in which KGF binding and receptor activation are dramatically effected by the presence or absence of various heparin-like proteoglycan extracellular matrix components have been identified, suggesting that heparin-like proteoglycans play a vital role in the KGF signaling pathway by enabling interaction with its high affinity receptor-tyrosine kinase in vivo.
