Mice Deficient in Hepsin, a Serine Protease, Exhibit Normal Embryogenesis and Unchanged Hepatocyte Regeneration Ability

Yu, I-Shing; Chen, Huei-Jane; Lee, Ying-Shuan E.; Huang, Pei-Hsing; Lin, Shu‐Rung; Tsai, Tzan-Wu; Lin, Shu‐Wha

doi:10.1055/s-0037-1614129

Cited by 45 publications

(50 citation statements)

References 22 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hepsin has been shown to activate pro-hepatocyte growth factor with the subsequent induction of cMet receptor tyrosine phosphorylation (16,24), a process known to promote cell growth. Analyses of Hepsin Ϫ/Ϫ mice identified no abnormalities in development, growth, fertility, viability, hemostasis, or liver cell regeneration (49,50,53). Corin, a TTSP expressed highly in the heart and at lower levels in testes and kidney (51), has been shown to process pro-atrial natriuretic peptide to its active form in vitro (52).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

Kim¹,

Heinlein²,

Hackman

et al. 2006

Molecular and Cellular Biology

218

193

View full text Add to dashboard Cite

Tmprss2 encodes an androgen-regulated type II transmembrane serine protease (TTSP) expressed highly in normal prostate epithelium and has been implicated in prostate carcinogenesis. Although in vitro studies suggest protease-activated receptor 2 may be a substrate for TMPRSS2, the in vivo biological activities of TMPRSS2 remain unknown. We generated Tmprss2 ؊/؊ mice by disrupting the serine protease domain through homologous recombination. Compared to wild-type littermates, Tmprss2 ؊/؊ mice developed normally, survived to adulthood with no differences in protein levels of prostatic secretions, and exhibited no discernible abnormalities in organ histology or function. Loss of TMPRSS2 serine protease activity did not influence fertility, reduce survival, result in prostate hyperplasia or carcinoma, or alter prostatic luminal epithelial cell regrowth following castration and androgen replacement. Lack of an observable phenotype in Tmprss2 ؊/؊ mice was not due to transcriptional compensation by closely related Tmprss2 homologs. We conclude that the lack of a discernible phenotype in Tmprss2 ؊/؊ mice suggests functional redundancy involving one or more of the type II transmembrane serine protease family members or other serine proteases. Alternatively, TMPRSS2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation.

show abstract

Section: Discussionmentioning

confidence: 99%

Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

Kim¹,

Heinlein²,

Hackman

et al. 2006

Molecular and Cellular Biology

218

193

View full text Add to dashboard Cite

show abstract

“…To date, the physiologic function of hepsin and its role in tumor development has not been fully elucidated. Hepsin-deficient mice have been shown to be viable, fertile, grow normally, and have no defect in liver function, demonstrating that hepsin is not essential for either embryonic development or maintenance of vital adult functions (22,23). Early in vitro experiments suggest that hepsin may play a role in tumor cell growth.…”

Section: Introductionmentioning

confidence: 99%

Antibodies Neutralizing Hepsin Protease Activity Do Not Impact Cell Growth but Inhibit Invasion of Prostate and Ovarian Tumor Cells in Culture

Xuan¹,

Schneider²,

Toy³

et al. 2006

Cancer Research

View full text Add to dashboard Cite

Hepsin is a type II transmembrane serine protease that is expressed in normal liver, and at lower levels in kidney, pancreas, and testis. Several studies have shown that hepsin mRNA is significantly elevated in most prostate tumors, as well as a significant fraction of ovarian and renal cell carcinomas and hepatomas. Although the overexpression of mRNA in these tumors has been extensively documented, there has been conflicting literature on whether hepsin plays a role in tumor cell growth and progression. Early literature implied a role for hepsin in human tumor cell proliferation, whereas recent studies with a transgenic mouse model for prostate cancer support a role for hepsin in tumor progression and metastases. To evaluate this issue further, we have expressed an activatable form of hepsin, and have generated a set of monoclonal antibodies that neutralize enzyme activity. The neutralizing antibodies inhibit hepsin enzymatic activity in biochemical and cell-based assays. Selected neutralizing and nonneutralizing antibodies were used in cell-based assays with tumor cells to evaluate the effect of antibodies on tumor cell growth and invasion. Neutralizing antibodies failed to inhibit the growth of prostate, ovarian, and hepatoma cell lines in culture. However, potent inhibitory effects of the antibodies were seen on invasion of ovarian and prostate cells in transwell-based invasion assays. These results support a role for hepsin in tumor cell progression but not in primary tumor growth. Consistent with this, immunohistochemical experiments with a mouse monoclonal antibody reveal progressively increased staining of prostate tumors with advanced disease, and in particular, extensive staining of bone metastatic lesions.

show abstract

“…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.…”

mentioning

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

Self Cite

View full text Add to dashboard Cite

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

show abstract

Mice Deficient in Hepsin, a Serine Protease, Exhibit Normal Embryogenesis and Unchanged Hepatocyte Regeneration Ability

Cited by 45 publications

References 22 publications

Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

Antibodies Neutralizing Hepsin Protease Activity Do Not Impact Cell Growth but Inhibit Invasion of Prostate and Ovarian Tumor Cells in Culture

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

Contact Info

Product

Resources

About