Generation and characterization of mice deficient in hepsin, a hepatic transmembrane serine protease.

Wu, Qingyu; Yu, Dihua; Post, J.; Halks-Miller, Meredith; Sadler, J. Evan; Morser, John

doi:10.1172/jci1617

Cited by 81 publications

(85 citation statements)

References 39 publications

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“…A proteolysis-independent role of HAI-1 in embryonic development has also been proposed (Tanaka et al, 2005), because HAI-1 is an integral transmembrane protein with a cytoplasmic tail domain that is potentially capable of transducing extracellular signals, and because hepatocyte growth factor activator, hepsin, and matriptase are all dispensable for mouse embryonic development (Wu et al, 1998;List et al, 2002;Itoh et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

et al. 2006

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Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a Kunitz-type transmembrane serine protease inhibitor that forms inhibitor complexes with several trypsin-like serine proteases and is required for mouse placental development and embryo survival. Here we show that the essential function of HAI-1 in placentation and all other embryonic processes is to restrict the activity of the type II transmembrane serine protease, matriptase. Enzymatic gene trapping of matriptase combined with HAI-1 immunohistochemistry revealed that matriptase is coexpressed with HAI-1 in both extraembryonic and embryonic tissues. As early as embryonic day 8.5, matriptase and HAI-1 were expressed in a population of chorionic trophoblasts. Ablation of HAI-1 disrupted the epithelial integrity of this cell population, causing disorganized laminin deposition and altered expression of E-cadherin and b-catenin. This led to a complete loss of undifferentiated chorionic trophoblasts after embryonic day 9.5 and prevented the formation of the placental labyrinth. Genetic ablation of matriptase activity in HAI-1-deficient embryos, however, restored the integrity of chorionic trophoblasts and enabled placental labyrinth formation and development to term. Furthermore, matriptase/HAI-1 double-deficient mice were phenotypically indistinguishable from matriptase single-deficient littermates.

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Section: Introductionmentioning

confidence: 99%

Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

et al. 2006

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“…8 In addition, hepsin colocalizes with desmoplakin at the sites of desmosomal junctions. 9 Previously, Wu et al 10 and our group 11 successfully deleted the hepsin gene (hepsin À/À ) in mice and generated hepsin À/À mice that are viable, fertile, and grow normally, suggesting that hepsin is not essential for normal development. No significant differences in coagulation function or liver regeneration ability were found in hepsin À/À and wild-type (WT) littermates.…”

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confidence: 99%

Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

Hsu

Huang

et al. 2012

Hepatology

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The liver architecture plays an important role in maintaining hemodynamic balance, but the mechanisms that underlie this role are not fully understood. Hepsin, a type II transmembrane serine protease, is predominantly expressed in the liver, but has no known physiological functions. Here, we report that hemodynamic balance in the liver is regulated through hepsin. Deletion of hepsin (hepsin 2/2 ) in mice resulted in enlarged hepatocytes and narrowed liver sinusoids. Using fluorescent microbeads and antihepsin treatment, we demonstrated that metastatic cancer cells preferentially colonized the hepsin 2/2 mouse liver as a result of the retention of tumor cells because of narrower sinusoids. The enlarged hepatocytes expressed increased levels of connexin, which resulted from defective prohepatocyte growth factor (pro-HGF) processing and decreased c-Met phosphorylation in the livers of hepsin 2/2 mice. Treatment of hepsin 2/2 mice with recombinant HGF rescued these phenotypes, and treatment of wild-type mice with an HGF antagonist recapitulated the phenotypes observed in hepsin 2/2 mice. Conclusion: Our findings show that the maintenance of hepatic structural homeostasis occurs through HGF/c-Met/connexin signaling by hepsin, and hepsin-mediated changes in liver architecture significantly enhance tumor metastasis to the liver. (HEPATOLOGY 2012;56:1913-1923 T ype II transmembrane serine proteases (TTSPs) have important physiological functions and pathological implications in iron metabolism, 1 blood pressure regulation, and metastasis of cancers. 2 More than 20 TTSPs exist and they are divided into four subfamilies. Among these families, the hepsin/ enteropeptidase subfamily is recognized structurally by a scavenger receptor cysteine-rich domain linked to a serine protease domain contained within an extracellular stem region. Although hepsin may be involved in the progression of several human cancers, 3 its physiological function has not yet been fully characterized. Hepsin is predominantly expressed in the liver. 4 Antisenseoligonucleotide blockade of hepsin affects cell growth and enlarges and flattens hepatoma cells. 5 Several in vitro studies have identified substrates for hepsin, including coagulation factor VII, 6 prohepatocyte growth factor (pro-HGF), 7 and prourokinase-type plasminogen activator. 8 In addition, hepsin colocalizes with desmoplakin at the sites of desmosomal junctions. 9

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“…Despite its expression in the very early stages of embryogenesis (2), hepsin-deficient mice were viable and developed normally (3,4). The studies further showed that hepsin was not essential for liver regeneration and for coagulationrelated physiological functions (3,4). However, hepsin has been implicated in ovarian cancer (5) and prostate cancer (6 -11), where several gene expression studies have identified it as one of the most highly induced genes.…”

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Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

Moran¹,

Li²,

Fan³

et al. 2006

Journal of Biological Chemistry

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Hepsin, a type II transmembrane serine protease, is strongly up-regulated in prostate cancer. Hepsin overexpression in a mouse prostate cancer model resulted in tumor progression and metastasis, associated with basement membrane disorganization. We investigated whether hepsin enzymatic activity was linked to the basement membrane defects by examining its ability to initiate the plasminogen/plasmin proteolytic pathway. Because plasminogen is not processed by hepsin, we investigated the upstream activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator. Enzymatic assays with a recombinant soluble form of hepsin demonstrated that hepsin did not cleave pro-tissue-type plasminogen activator but efficiently converted pro-uPA into high molecular weight uPA by cleavage at the Lys 158 -Ile 159 (P 1 -P 1 ) peptide bond. uPA generated by hepsin displayed enzymatic activity toward small synthetic and macromolecular substrates indistinguishable from uPA produced by plasmin. The catalytic efficiency of pro-uPA activation by hepsin (k cat /K m 4.8 ؋ 10 5 M ؊1 s ؊1 ) was similar to that of plasmin, which is considered the most potent pro-uPA activator and was about 6-fold higher than that of matriptase. Conversion of pro-uPA was also demonstrated with cell surface-expressed full-length hepsin. A stable hepsinoverexpressing LnCaP cell line converted pro-uPA into high molecular weight uPA at a rate of 6.6 ؎ 1.9 nM uPA h ؊1 , which was about 3-fold higher than LnCaP cells expressing lower hepsin levels on their surface. In conclusion, the ability of hepsin to efficiently activate pro-uPA suggests that it may initiate plasmin-mediated proteolytic pathways at the tumor/stroma interface that lead to basement membrane disruption and tumor progression.Hepsin is a type II transmembrane serine protease expressed on the surface of epithelial cells. The 417-amino acid protein is composed of a short N-terminal cytoplasmic domain, a transmembrane domain, and a single scavenger receptor cysteinerich domain that packs tightly against the C-terminal protease domain (1). The physiologic function of hepsin remains unknown. Despite its expression in the very early stages of embryogenesis (2), hepsin-deficient mice were viable and developed normally (3, 4). The studies further showed that hepsin was not essential for liver regeneration and for coagulationrelated physiological functions (3, 4). However, hepsin has been implicated in ovarian cancer (5) and prostate cancer (6 -11), where several gene expression studies have identified it as one of the most highly induced genes. Hepsin RNA levels were found to be low in normal prostate and benign hyperplasia but strongly increased in prostate carcinoma, particularly in advanced stages (8 -10). Hepsin protein staining with a monoclonal anti-hepsin antibody showed that hepsin expression was highest at sites of bone metastasis and in late stage primary tumors (12), which is consistent with the finding that increased hepsin RNA levels correlated with higher Gleason grades...

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Generation and characterization of mice deficient in hepsin, a hepatic transmembrane serine protease.

Cited by 81 publications

References 39 publications

Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice

Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin

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