Simultaneous activation and hepatocyte growth factor activator inhibitor 1-mediated inhibition of matriptase induced at activation foci in human mammary epithelial cells

Lee, Ming-Shyue; Kiyomiya, Ken-ichi; Benaud, Christelle; Dickson, Robert B.; Lin, Chen‐Yong

doi:10.1152/ajpcell.00497.2004

Cited by 74 publications

(93 citation statements)

References 31 publications

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“…The challenge of defining the key matriptase substrates has been hampered by the surprising subsequent events associated with matriptase activation and locations at which matriptase activation takes place. Matriptase activation is tightly coupled to its inhibition by HAI-1 (19). The prompt inhibition by HAI-1 of active matriptase right after its activation implies that the active matriptase has only a very short period of time to act on its substrates before being inhibited by HAI-1.…”

Section: Discussionmentioning

confidence: 99%

“…The term "matriptase activation machinery" has been used to describe this complex matriptase activation system that must anchor on the cell membrane to perform two major biochemical events: 1) mediating the proteolytic cleavage of matriptase, which converts the single-chain matriptase zymogen into the two-chain active enzyme and 2) inhibition of the newly formed active matriptase through high affinity binding to HAI-1 resulting in the formation of a 120-kDa matriptase-HAI-1 complex (16). Many protease inhibitors are physically separated from their target proteases, and the colocalization of HAI-1 with matriptase is quite unusual (18,19). The close spatial relationship of the two proteins, the presence of HAI-1 at significantly higher concentrations than matriptase, and the high affinity nature of the binding between active matriptase and HAI-1, results in HAI-1 binding and inhibition of matriptase proteolytic activity almost immediately after the enzyme is activated.…”

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confidence: 99%

“…Instead, breast cancer cells activate matriptase constitutively (30). Suramin, a sulfide-rich polyanionic compound, can stimulate matriptase activation in a variety of matriptase-expressing cells (19). These unrelated chemicals act through different mechanisms and induce different signal pathways, all of which converge at the matriptase activation machinery and induce matriptase activation and inhibition.…”

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Matriptase Activation, an Early Cellular Response to Acidosis

Tseng

Chou

et al. 2010

Journal of Biological Chemistry

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Extracellular acidosis often rapidly causes intracellular acidification, alters ion channel activities, and activates G proteincoupled receptors. In this report, we demonstrated a novel cellular response to acidosis: induction of the zymogen activation of matriptase. Acid-induced matriptase activation is ubiquitous among epithelial and carcinoma cells and is characterized by rapid onset, fast kinetics, and the magnitude of activation seen. Trace amounts of activated matriptase can be detected 1 min after cells are exposed to pH 6.0 buffer, and the vast majority of latent matriptase within the cells is converted to activated matriptase within 20 min. Matriptase activation may be a direct response to proton exposure because acid-induced matriptase activation also occurs in an in vitro, cell-free setting in which intracellular signaling molecules and ion channel activities are largely absent. Acid-induced matriptase activation takes place both on the cell surface and inside the cells, likely due to the parallel intracellular acidification that activates intracellular matriptase. Following matriptase activation, the active enzyme is immediately inhibited by binding to hepatocyte growth factor activator inhibitor 1, resulting in stable matriptase-hepatocyte growth factor activator inhibitor 1 complexes that are rapidly secreted. As an early response to acidosis, matriptase activation can also be induced by perturbation of intracellular pH homeostasis by 5-(N-methyl-N-isobutyl)-amiloride and 5-(N-ethyl-Nisopropyl)-amiloride, both of which inhibit Na ؉ /H ؉ exchangers, and diisothiocyanostilbene-2,2-disulfonic acid, which can inhibit other acid-base ion channels. This study uncovers a novel mechanism regulating proteolysis in epithelial and carcinoma cells, and also demonstrates that a likely function of matriptase is as an early response to acidosis.Matriptase, a type 2 transmembrane serine protease, is broadly expressed by epithelial and carcinoma cells (1-3), and plays essential roles in the maintenance of epithelial integrity, particularly for epidermal terminal differentiation and barrier function (4 -6). A rare human inherited genetic disorder, autosomal recessive ichthyosis, is associated with two missense mutations of the human ST14 gene, which encodes matriptase (7,8). In addition, the protease can exhibit potent oncogenic activity via ras-dependent and ras-independent pathways when it is even slightly overexpressed in the skin of transgenic mice (9). Several tumor xenograft models also provide further evidence that matriptase is strongly associated with cancer cell proliferation, invasion, and metastasis (10, 11). As is typical for classical serine proteases, matriptase is synthesized as a zymogen and must undergo activation by cleavage at Arg 614 (R2VVGG) to gain full proteolytic activity. It is the activity of the mature enzyme that is believed to be responsible for both the physiological and pathological functions of the enzyme identified by studies of animal models and human genetics (12)(13)(14).In contr...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Matriptase Activation, an Early Cellular Response to Acidosis

Tseng

Chou

et al. 2010

Journal of Biological Chemistry

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“…mammary epithelial cells to sphingosine-1-phosphate (see below) leads to the rapid translocation of matriptase to the cell surface and a subsequent activation in an actin cytoskeleton remodeling-dependent manner (13). The extracellular stem region of matriptase consists of a single SEA (residues 86-201), 2 CUB (residues 214-334 and 340-447), and 4 LDLRA (residues 452-486, 487-523, 524-561, and 566-604) domains.…”

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Matriptase: Potent Proteolysis on the Cell Surface

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Bugge

Szabo

2006

Mol Med

142

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“…1). 5,7,9,10 HAI-1 is expressed in many epithelialderived tissues including bile duct. 11 HAI-2 is an isoform of HAI-1, which is colocalized with HAI-1 in most epithelia, and also detected in nonepithelial cells of the brain and lymph nodes, 9 suggesting that HAI-2 may have a nonredundant role.…”

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Persistent elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fibrosis and differentiation

et al. 2011

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Alteration of cell surface proteolysis has been proposed to play a role in liver fibrosis, a grave complication of biliary atresia (BA). In this study we investigated the roles of hepatocyte growth factor activator inhibitor (HAI)-1 and -2 in the progression of BA. The expression levels of HAI-1 and -2 were significantly increased in BA livers compared with those in neonatal hepatitis and correlated with disease progression. In BA livers, HAI-1 and -2 were coexpressed in cells involved in ductular reactions. In other selective cholangiopathies, ductular cells positive for HAI-1 or HAI-2 also increased in number. Inflammatory cytokines, growth factors, and bile acids differentially up-regulated expression of HAI-1 and -2 transcripts in fetal liver cells and this induction could be antagonized by a cyclooxygenase-2 inhibitor. Conditioned media from cell lines stably overexpressing HAI-1 or HAI-2 enhanced the fibrogenic activity of portal fibroblasts and stellate cells, suggesting that both proteins might be involved in liver fibrosis. Because HAI-1 and -2 colocalized in ductular reactions sharing similar features to those observed during normal liver development, we sought to investigate the role of HAI-1 and -2 in cholangiopathies by exploring their functions in fetal liver cells. Knockdown of HAI-1 or HAI-2 promoted bidirectional differentiation of hepatoblast-derived cells. In addition, we showed that the hepatocyte growth factor activator, mitogen-activated protein kinase kinase 1, and phosphatidylinositol 3-kinase signaling pathways were involved in hepatic differentiation enhanced by HAI-2 knockdown. Conclusion: HAI-1 and -2 are overexpressed in the liver in cholangiopathies with ductular reactions and are possibly involved in liver fibrosis and hepatic differentiation; they could be investigated as disease markers and potential therapeutic targets. (HEPATOLOGY 2012;55:161-172)

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Simultaneous activation and hepatocyte growth factor activator inhibitor 1-mediated inhibition of matriptase induced at activation foci in human mammary epithelial cells

Abstract: Lee, Ming-Shyue, Ken-ichi Kiyomiya, Christelle Benaud, Robert B. Dickson, and Chen-Yong Lin. Simultaneous activation and hepatocyte growth factor activator inhibitor 1-mediated inhibition of matriptase induced at activation foci in human mammary epithelial cells.

Cited by 74 publications

References 31 publications

Matriptase Activation, an Early Cellular Response to Acidosis

Matriptase Activation, an Early Cellular Response to Acidosis

Matriptase: Potent Proteolysis on the Cell Surface

Persistent elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fibrosis and differentiation

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