Characterization of a functional relationship between hepatocyte growth factor and mouse bone marrow-derived mast cells

Fehlner-Gardiner, Christine; Cao, Henian; Jackson-Boeters, Linda; Nakamura, Toshikazu; Elliott, Bruce E.; Uniyal, Shashi; Chan, Bosco M.C.

doi:10.1046/j.1432-0436.1999.6510027.x

Cited by 10 publications

(13 citation statements)

References 89 publications

(121 reference statements)

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“…The present data suggest an explanation for the observation that a product of in vitro differentiated mouse mast cells degrades the HGF α chain (18). Our data indicate that a particular mouse chymase, MCP4, hydrolyzes HGF in a pattern similar to that generated by the complex mixture of biomolecules released by degranulating mast cells.…”

Section: Discussionsupporting

confidence: 57%

“…Other investigations have established that a human mast cell line (HMC-1) and in vitro differentiated mouse mast cells express HGF receptor c-met and respond to HGF (18,39). In HMC-1 cells, c-met expression is inducible and exposure to HGF suppresses release of tumor necrosis factor-α (39).…”

Section: Discussionmentioning

confidence: 99%

“…In HMC-1 cells, c-met expression is inducible and exposure to HGF suppresses release of tumor necrosis factor-α (39). In bone marrow-derived mouse mast cells, HGF promotes developmental stage-and integrin-dependant migration (18). Thus, secreted mast cell chymase and cathepsin G may decrease cytokine release and migration responses to HGF in the vicinity of a degranulating mast cell.…”

Section: Discussionmentioning

confidence: 99%

“…Murine mast cell precursors express c-met during in vitro differentiation (18) and respond to HGF with β1 integrin-mediated migration. By releasing heparin, mast cells may raise circulating HGF after thrombotic events, like myocardial infarction (19).…”

mentioning

confidence: 99%

“…Thus, HGF may influence mast cell behavior and vice versa. In this regard, it is notable that secreted products of in vitro differentiated mast cells ablate HGF activity (18).…”

mentioning

confidence: 99%

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

Raymond

Cruz

Caughey

2006

Journal of Biological Chemistry

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Hepatocyte growth factor (HGF) is a plasminogen-like protein with an α chain linked to a trypsinlike 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, Leu 480 , 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.HGF 2 is a mitogen, motogen, and morphogen for epithelial and mesenchymal cells (1). It is also known as scatter factor because it disperses epithelial cells in culture (2). Genetic deletion in mice suggests that HGF is critical for embryonic development (3). Adult mesenchymal cells also produce HGF, which is thought to regulate tissue regeneration and repair after injury (4, 5), epithelial to mesenchymal transitions, and formation of vessels and other tube-like structures (6). HGF production is inducible. Circulating levels rise markedly in several types of tissue injury, as in liver damage (7), arterial thrombosis (8), or acute rejection of a transplanted lung (9). When used as a drug, HGF stimulates lung regrowth after pneumonectomy (10), diminishes lung fibrosis (11) and allergic airway remodeling (12), and The present work focuses on major inflammatory cell peptidases, including the human mast cell chymotryptic peptidase, chymase, a mouse enzyme, mast cell protease (MCP)4, with similar tissue distribution and enzymatic properties (20)(21)(22), and human neutrophil elastase and cathepsin G. Cathepsin G possesses tryptic, chymotryptic, and metase activity (23) and is expressed by mast cells as well as by neutrophils. Human chymase and cathepsin G are expressed in a subset of mast cells inhabiting the dermis and certain oth...

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…Thus, HGF may influence mast cell behavior and vice versa. In this regard, it is notable that secreted products of in vitro differentiated mast cells ablate HGF activity (18).…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

Raymond

Cruz

Caughey

2006

Journal of Biological Chemistry

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Constitutive activation of met kinase in non‐small‐cell lung carcinomas correlates with anchorage‐independent cell survival

Qiao

Hung

Tremblay

et al. 2002

J of Cellular Biochemistry

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Lung cancer is currently the most frequent cause of cancer death in North America. Hepatocyte growth factor (HGF) and its receptor Met are frequently over-expressed in non-small-cell lung carcinomas (NSCLC), but their potential role in tumor progression is not clearly known. To assess the role of HGF/Met signaling in lung carcinomas, we have examined the expression, activation status, and function of Met in NSCLC cell lines (n = 7), established from primary tumors or pleural fluids of cancer patients. We observed Met expression in three NSCLC cell lines, two of which exhibited constitutive tyrosine-phosphorylation of Met, and Met kinase activity. In addition, the observed constitutive activation of Met was sustained under anchorage-independent conditions, and correlated with phosphatidyl inositol 3-kinase-dependent cell survival. Immunoreactive HGF-like protein was secreted by two Met-positive and two Met-negative NSCLC cell lines. However HGF activity, as determined by the ability to induce cell scattering and tyrosine-phosphorylation of Met in reporter cell lines, was detected in conditioned medium from only one Met-negative NSCLC cell line: none of the conditioned media from Met-expressing NSCLC cell lines showed detectable HGF activity. Thus, constitutive activation of Met in NSCLC cell lines may occur at least in part through intracrine, or HGF-independent mechanisms. Interestingly, additional paracrine stimulation with exogenous recombinant HGF was required for DNA synthesis and correlated with increased activation of ERK1/2 in all Met-positive NSCLC cell lines, regardless of the basal activation status of Met. These findings indicate that a medium level of constitutive activation of Met occurs in some NSCLC cell lines, and correlates with survival of detached carcinoma cells; whereas additional paracrine stimulation by recombinant HGF is required for DNA synthesis. Thus constitutive and paracrine activation of Met may provide complementary signals that promote survival and proliferation, respectively, during tumor progression of NSCLC.

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Src and FAK mediate cell–matrix adhesion‐dependent activation of met during transformation of breast epithelial cells

Hui

Meens

Schick

et al. 2009

J of Cellular Biochemistry

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Cell-matrix adhesion has been shown to promote activation of the hepatocyte growth factor receptor, Met, in a ligand-independent manner. This process has been linked to transformation and tumorigenesis in a variety of cancer types. In the present report, we describe a key role of integrin signaling via the Src/FAK axis in the activation of Met in breast epithelial and carcinoma cells. Expression of an activated Src mutant in non-neoplastic breast epithelial cells or in carcinoma cells was found to increase phosphorylation of Met at regulatory tyrosines in the auto-activation loop domain, correlating with increased cell spreading and filopodia extensions. Furthermore, phosphorylated Met is complexed with beta1 integrins and is co-localized with vinculin and FAK at focal adhesions in epithelial cells expressing activated Src. Conversely, genetic or pharmacological inhibition of Src abrogates constitutive Met phosphorylation in carcinoma cells or epithelial cells expressing activated Src, and inhibits filopodia formation. Interestingly, Src-dependent phosphorylation of Met requires cell-matrix adhesion, as well as actin stress fiber assembly. Phosphorylation of FAK by Src is also required for Src-induced Met phosphorylation, emphasizing the importance of the Src/FAK signaling pathway. However, stimulation of Met phosphorylation by addition of exogenous HGF in epithelial cells is refractory to inhibition of Src family kinases, indicating that HGF-dependent and Src/integrin-dependent Met activation occur via distinct mechanisms. Together these findings demonstrate a novel mechanism by which the Src/FAK axis links signals from the integrin adhesion complex to promote Met activation in breast epithelial cells.

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Characterization of a functional relationship between hepatocyte growth factor and mouse bone marrow-derived mast cells

Cited by 10 publications

References 89 publications

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

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

Constitutive activation of met kinase in non‐small‐cell lung carcinomas correlates with anchorage‐independent cell survival

Src and FAK mediate cell–matrix adhesion‐dependent activation of met during transformation of breast epithelial cells

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