Abstract
Hepatocyte growth factor (HGF) exhibits mitogenic and/or motogenic activities for a variety of cells (see for review Matsumoto and Nakamura, 1992). Structurally, it has similarities to kringle-containing serine-proteases, although it does not possess proteolytic activity. The HGF receptor (HGFr) is the product of the c-met proto-oncogene, a membrane-spanning tyrosine kinase receptor. The 190-kDa precursor is proteolytically processed within the extra-cellular domain (ECD) to a heterodimer consisting of a 50-kDa α subunit disufide-linked to a 145-kDa β subunit. A structure-activity relationship analysis of both HGF and its receptor was performed by functional analysis of ligand and receptor variants.
I. Analysis of HGF variants was accomplished by defining their ability to induce DNA synthesis on hepatocytes in primary culture and to compete with wild-type HGF for binding to a soluble form of the HGFr (sHGFr: ECD fused to the hinge and constant region of human IgG heavy chain). Our results show that 1) Pro-HGF can bind to, but not activate the HGF receptor (HGFr); 2) the HGF β-chain is not required for receptor binding but contributes to receptor activation; 3) a primary receptor binding determinant is located within the N-terminal 272 residues.
II. Like the mature form of the HGFr, sHGFr is a heterodimer which arises by proteolytic processing. The putative cleavage site for the HGFr is 303-RKKKRS-308. Mutational analysis of this cleavage site suggests that HGFr maturation is mediated by furin or a furin-like protease. Finally, our data indicate that processing of the sHGFr into α/β form is not required for high affinity binding to either pro- or mature HGF.
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© 1993 Springer-Verlag Berlin Heidelberg
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Lokker, N.A., Mark, M.R., Godowski, P.J. (1993). Structure-Function Analysis of Hepatocyte Growth Factor and its Tyrosine-Kinase Receptor c-Met. In: Heilmeyer, L.M.G. (eds) Tyrosine Phosphorylation/Dephosphorylation and Downstream Signalling. NATO ASI Series, vol 76. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-78247-3_8
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DOI: https://doi.org/10.1007/978-3-642-78247-3_8
Publisher Name: Springer, Berlin, Heidelberg
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