Online citations, reference lists, and bibliographies.
Please confirm you are human
(Sign Up for free to never see this)
← Back to Search

Mast Cell And Neutrophil Peptidases Attack An Inactivation Segment In Hepatocyte Growth Factor To Generate NK4-like Antagonists*

W. Raymond, A. Cruz, G. Caughey
Published 2006 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Hepatocyte growth factor (HGF) is a plasminogen-like protein with an α chain linked to a trypsin-like β 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 α 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 α chain on the N-terminal side of the cysteine linking the α and β 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.
This paper references
HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor
K. Date (1997)
Mammalian chymotrypsin-like enzymes. Comparative reactivities of rat mast cell proteases, human and dog skin chymases, and human cathepsin G with peptide 4-nitroanilide substrates and with peptide chloromethyl ketone and sulfonyl fluoride inhibitors.
J. Powers (1985)
Quantum proteolysis by neutrophils: implications for pulmonary emphysema in alpha 1-antitrypsin deficiency.
E. Campbell (1999)
Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor
Y. Uehara (1995)
Hepatocyte growth factor and keratinocyte growth factor in the pulmonary edema fluid of patients with acute lung injury. Biologic and clinical significance.
G. Verghese (1998)
Mouse mast cell protease-1 cleaves angiotensin I to form angiotensin II.
Kayo Saito (2003)
The Chymase, Mouse Mast Cell Protease 4, Constitutes the Major Chymotrypsin-like Activity in Peritoneum and Ear Tissue. A Role for Mouse Mast Cell Protease 4 in Thrombin Regulation and Fibronectin Turnover
E. Tchougounova (2003)
NK4 (HGF‐antagonist/angiogenesis inhibitor) in cancer biology and therapeutics
K. Matsumoto (2003)
Distinct Multisite Synergistic Interactions Determine Substrate Specificities of Human Chymase and Rat Chymase-1 for Angiotensin II Formation and Degradation*
S. Sanker (1997)
A functional domain in the heavy chain of scatter factor/hepatocyte growth factor binds the c-Met receptor and induces cell dissociation but not mitogenesis.
G. Hartmann (1992)
Met, metastasis, motility and more
C. Birchmeier (2003)
Prediction of lung-transplant rejection by hepatocyte growth factor
S. Aharinejad (2004)
Roles of Hepatocyte Growth Factor and Mast Cells in Thrombosis and Angiogenesis
A. Matsumori (2004)
Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice.
Y. Sakamaki (2002)
Specificity of human cathepsin G.
J. Polanowska (1998)
Thrombosis Increases Circulatory Hepatocyte Growth Factor by Degranulation of Mast Cells
M. Kinoshita (2002)
Hepatocyte Growth Factor Suppresses Vascular Medial Hyperplasia and Matrix Accumulation in Advanced Pulmonary Hypertension of Rats
M. Ono (2004)
Characterization of a functional relationship between hepatocyte growth factor and mouse bone marrow-derived mast cells.
C. C. Fehlner-Gardiner (1999)
Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development
E. Sonnenberg (1993)
Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF.
T. Nakamura (2000)
Cleavage of Type I Procollagen by Human Mast Cell Chymase Initiates Collagen Fibril Formation and Generates a Unique Carboxyl-terminal Propeptide*
M. Kofford (1997)
New developments in the genetics and activation of mast cell proteases.
G. Caughey (2002)
Simultaneous or delayed administration of hepatocyte growth factor equally represses the fibrotic changes in murine lung injury induced by bleomycin. A morphologic study.
M. Yaekashiwa (1997)
Hepatocyte growth factor attenuates airway hyperresponsiveness, inflammation, and remodeling.
W. Ito (2005)
Extended Substrate Specificity of Rat Mast Cell Protease 5, a Rodent α-Chymase with Elastase-like Primary Specificity*
U. Karlson (2003)
Cooperative Interaction between α- and β-Chains of Hepatocyte Growth Factor on c-Met Receptor Confers Ligand-induced Receptor Tyrosine Phosphorylation and Multiple Biological Responses*
K. Matsumoto (1998)
Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases
C. Owen (1995)
Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure.
E. Gohda (1988)
Angiotensin II generation by mast cell α- and β-chymases
G. Caughey (2000)
Identification of a competitive HGF antagonist encoded by an alternative transcript.
A. Chan (1991)
Detection of MCT and MCTC types of human mast cells by immunohistochemistry using new monoclonal anti-tryptase and anti-chymase antibodies.
A. Irani (1989)
Albumin Is a Substrate of Human Chymase
W. Raymond (2003)
The HMC-1 human mast cell line expresses the hepatocyte growth factor receptor c-met.
K. Yano (1997)
Rodent α‐chymases are elastase‐like proteases
Y. Kunori (2002)
Hepatocyte growth factor may act as a pulmotrophic factor on lung regeneration after acute lung injury.
K. Yanagita (1993)
Activation of human interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond by mast cell chymase.
J. Saarinen (1994)
Distribution of chymase-containing mast cells in human bronchi.
R. Matin (1992)
Evidence for the identity of human scatter factor and human hepatocyte growth factor.
K. M. Weidner (1991)
Cloning of the cDNA and gene for mouse mast cell protease 4. Demonstration of its late transcription in mast cell subclasses and analysis of its homology to subclass-specific neutral proteases of the mouse and rat.
W. Serafin (1991)

This paper is referenced by
Alternative proteolytic processing of hepatocyte growth factor during wound repair.
Nils Buchstein (2009)
Mast cell peptidases: chameleons of innate immunity and host defense.
N. Trivedi (2010)
Increased production and secretion of HGF α‐chain and an antagonistic HGF fragment in a human breast cancer progression model
T. G. Wright (2009)
Angioinhibitory Action of NK4 Involves Impaired Extracellular Assembly of Fibronectin Mediated by Perlecan-NK4 Association*
K. Sakai (2009)
This information is current as Lost Efficiency during Primate Evolution Cathepsin G Gained Tryptic Function but How Immune Peptidases Change Specificity :
Wilfred W. Raymond (2010)
Discovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors.
D. Zhang (2012)
The αvβ6 integrin modulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells.
K. Sugimoto (2012)
Inhibition of Met/HGF receptor and angiogenesis by NK4 leads to suppression of tumor growth and migration in malignant pleural mesothelioma
Y. Suzuki (2010)
Mast Cells in Kidney Regeneration
E. Daugas (2011)
How Immune Peptidases Change Specificity: Cathepsin G Gained Tryptic Function but Lost Efficiency during Primate Evolution
W. Raymond (2010)
Discriminating between the activities of human cathepsin G and chymase using fluorogenic substrates
B. Korkmaz (2011)
Analysis of mast cell mediated immune response to Listeria monocytogenes.
McCall-Culbreath Kd (2008)
HGF/Met Signaling Is a Key Player in Malignant Mesothelioma Carcinogenesis
G. Gaudino (2014)
Structural basis for agonism and antagonism of hepatocyte growth factor
W. Tolbert (2010)
High concentration but low biological activity of hepatocyte growth factor in patients with chronic renal failure
J. Lönn (2012)
Effets des clivages du récepteur tyrosine kinase Met par les calpaïnes sur la motilité et la mort cellulaire
Rémi Montagne (2014)
Hepatocyte growth factor and lung fibrosis.
B. Crestani (2012)
Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors.
D. Zhang (2013)
Paradoxical action of growth factors: antiproliferative and proapoptotic signaling by HGF/c-MET
B. Grzelakowska-Sztabert (2011)
Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of rheumatoid arthritis
Sachi Tsunemi (2013)
Mast cell proteases.
G. Pejler (2007)
during Primate Evolution Tryptic Function but Lost Efficiency Specificity: Cathepsin G Gained How Immune Peptidases Change
C. Craik (2010)
Mutational Tail Loss Is an Evolutionary Mechanism for Liberating Marapsins and Other Type I Serine Proteases from Transmembrane Anchors*
K. Raman (2013)
Chapter 590 – Chymases
G. Caughey (2013)
Identification of Mannose Receptor as Receptor for Hepatocyte Growth Factor β-Chain
H. Ohnishi (2012)
Expression of the HGF receptor c‐met by macrophages in experimental autoimmune encephalomyelitis
M. Moransard (2010)
Infiltrating Mast Cell–Mediated Stimulation of Estrogen Receptor Activity in Breast Cancer Cells Promotes the Luminal Phenotype
Maria Teresa Majorini (2020)
Pyridazinone derivatives displaying highly potent and selective inhibitory activities against c-Met tyrosine kinase.
Y. Liu (2016)
Regulation of Hepatocyte Growth Factor in Mice with Pneumonia by Peptidases and Trans-Alveolar Flux
W. Raymond (2015)
Crosstalk between the alpha2beta1 integrin and c-met/HGF-R regulates innate immunity.
K. McCall-Culbreath (2008)
Mast cell proteases as pharmacological targets.
G. Caughey (2016)
Semantic Scholar Logo Some data provided by SemanticScholar