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J. Biol. Chem. 281 (3): 1489-1494

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Mast Cell and Neutrophil Peptidases Attack an Inactivation Segment in Hepatocyte Growth Factor to Generate NK4-like Antagonists*

Wilfred W. Raymond{ddagger}§, Anthony C. Cruz{ddagger}§, , and George H. Caughey{ddagger}§1

{ddagger}Department of Medicine and Cardiovascular Research Institute, The University of California at San Francisco, San Francisco, California 94143 and §The Veterans Affairs Medical Center, San Francisco, California 94121

Abstract: Hepatocyte growth factor (HGF) is a plasminogen-like protein with an {alpha} chain linked to a trypsin-like beta chain without peptidase activity. The interaction of HGF with c-met, a receptor tyrosine kinase expressed by many cells, is important in cell growth, migration, and formation of endothelial and epithelial tubes. Stimulation of c-met requires two-chain, disulfide-linked HGF. Portions of an {alpha} chain containing an N-terminal segment and four kringle domains (NK4) antagonize HGF activity. Until now, no physiological pathway for generating NK4 was known. Here we show that chymases, which are chymotryptic peptidases secreted by mast cells, hydrolyze HGF, thereby abolishing scatter factor activity while generating an NK4-like antagonist of HGF scatter factor activity. Thus, chymase interferes with HGF directly by destroying active protein and indirectly by generating an antagonist. The site of hydrolysis, Leu480, lies in the {alpha} chain on the N-terminal side of the cysteine linking the {alpha} and beta chains. This site appears to be specific for HGF because chymase does not hydrolyze other plasminogen-like proteins, such as macrophage-stimulating protein and plasminogen itself. Mast cell/neutrophil cathepsin G and neutrophil elastase generate similar fragments of HGF by cleaving near the chymase site. Mast cell and neutrophil peptidases are secreted during tissue injury, infection, ischemia, and allergic inflammation, where they may oppose HGF effects on epithelial repair. Thus, HGF possesses an "inactivation segment" that serves as an Achilles' heel attacked by inflammatory proteases. This work reveals a potential physiological pathway for inactivation of HGF and generation of NK4-like antagonists.

Received for publication October 13, 2005. Revision received November 22, 2005.

* This work was supported by Grant HL024136 from the National Institutes of Health and by the Northern California Institute for Research and Education. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence should be addressed: Veterans Affairs Medical Center 111-D, 4150 Clement St., San Francisco, CA 94121; Tel.: 415-221-4810 (ext. 2385); Fax: 415-387-3568; E-mail: George.Caughey{at}ucsf.edu.

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