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Sci. STKE, 24 January 2006
Vol. 2006, Issue 319, p. tw38
[DOI: 10.1126/stke.3192006tw38]

EDITORS' CHOICE

BIOCHEMISTRY HGF Cleaved into an Antagonist

Hepatocyte growth factor (HGF) is a disulfide-linked dimer of α and β subunits similar to plasminogen. A fragment of the α subunit consisting of the N-terminal hairpin and four kringle domains (NK4) antagonizes the activity of HGF at its receptor c-met, a receptor tyrosine kinase. But is this fragment generated in vivo, and what enzymes would be responsible for this cleavage? Raymond et al. report that NK4 was generated in vitro from purified proteases that are secreted by mast cells and neutrophils. Purified human HGF was cleaved by chymase, cathepsin G, and neutrophil elastase, which are released during various types of inflammation, including allergic reactions. Mass spectrometry of the cleavage products identified an inactivation domain in the α subunit where all of the cleavage events occurred. The chymase-generated NK4 fragment inhibited the activity of HGF in an assay using Madin-Darby canine kidney cells. Thus, inflammation may trigger inactivation of HGF, which is important for endothelial and epithelial growth, migration, and tube formation, by two methods: cleavage of the active HGF dimer and production of an antagonistic fragment that blocks the activity of any uncleaved HGF.

W. W. Raymond, A. C. Cruz, G. H. Caughey, Mast cell and neutrophil peptidases attack an inactivation segment in hepatocyte growth factor to generate NK4-like antagonists. J. Biol. Chem. 281, 1489-1494 (2006). [Abstract] [Full Text]

Citation: HGF Cleaved into an Antagonist. Sci. STKE 2006, tw38 (2006).


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