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Heparin binding and oligomerization of hepatocyte growth factor/scatter factor isoforms. Heparan sulfate glycosaminoglycan requirement for Met binding and signaling.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 1997 Apr 04; Vol. 272 (14), pp. 9457-63. - Publication Year :
- 1997
-
Abstract
- Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding polypeptide that stimulates cell proliferation, motility, and morphogenesis by activation of its receptor, the c-Met tyrosine kinase. HGF/SF consists of a series of structural units, including an amino-terminal segment with a hairpin loop, four kringle domains, and a serine protease-like region. In this study, we demonstrate that the amino-terminal (N) domain retains the heparin-binding properties of full-length HGF/SF. In contrast to a previous hypothesis, selected basic amino acid residues in the hairpin loop are not critical for heparin binding, although alanine substitution at a subset of these sites markedly reduced the biological activity of the HGF/SF isoform, HGF/NK1. Covalent cross-linking experiments performed with wild-type and heparan sulfate glycosaminoglycan (HSGAG)-deficient Chinese hamster ovary (CHO) cells revealed that Met-HGF/NK1 binding was strongly dependent on HSGAG. Addition of heparin to HSGAG-deficient CHO cells not only restored ligand binding, but also increased ligand-dependent Met tyrosine phosphorylation and c-fos expression. Moreover, our results showed that heparin stimulated ligand oligomerization through an interaction with the N domain. These findings establish the importance of the N domain for heparin-ligand and ligand-ligand interactions, and demonstrate a crucial role for HSGAG in receptor binding and signal transduction.
- Subjects :
- Amino Acid Sequence
Animals
Circular Dichroism
Cricetinae
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Protein Conformation
Proto-Oncogene Proteins c-met
Structure-Activity Relationship
Heparin metabolism
Heparitin Sulfate metabolism
Hepatocyte Growth Factor metabolism
Methionine metabolism
Receptor Protein-Tyrosine Kinases metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 272
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9083085
- Full Text :
- https://doi.org/10.1074/jbc.272.14.9457