Complete nucleotide sequence, origin of isoform and functional characterization of the mouse hepsin gene

Kawamura, Shunsuke; Kurachi, Sumiko; Deyashiki, Yoshihiro; Kurachi, Kotoku

doi:10.1046/j.1432-1327.1999.00431.x

Cited by 13 publications

(19 citation statements)

References 39 publications

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“…Normal ovaries with epithelial inclusion cysts and the ovarian cancer tissue microarray, consisting of 70 ovarian carcinoma cores flanked with normal liver cores, were immunostained with a rabbit polyclonal antibody raised against a synthetic peptide (aa 241–260) that corresponds to the extracellular domain of human hepsin. Consistent with reports of high levels of hepsin expression in the normal liver,6, 31 hepsin protein was detected in the cytoplasm and membrane of hepatocytes (Fig. 1 a ).…”

Section: Resultssupporting

confidence: 91%

“…Hepsin is likely to be synthesized as a single chain zymogen and cleaved by an unknown enzyme to generate the mature, disulfide‐linked 2‐chain form 4. In addition to the catalytic domain, which includes the active site triad residues of His, Asp and Ser, hepsin protein is characterized by a macrophage scavenger receptor‐like domain of unknown function, a transmembrane domain and a short cytoplasmic domain 1–7. An alternatively‐spliced, nontransmembrane isoform of human hepsin was recently identified 8…”

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confidence: 99%

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Hepsin colocalizes with desmosomes and induces progression of ovarian cancer in a mouse model

Miao

Ergel

et al. 2008

Intl Journal of Cancer

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Hepsin is a serine protease that is widely expressed in different tissues and cell types, most prominently in the normal liver and kidney. Overexpression of hepsin has been associated with prostate cancers, ovarian cancers and renal cell carcinomas. The physiological functions of hepsin in normal tissues and tumors are poorly understood. To gain insight into its function in ovarian cancer, we analyzed the expression and subcellular localization of hepsin protein in ovarian cancer cell lines and tumors. We showed that the membrane-associated hepsin protein is present at desmosomal junctions, where it colocalizes with its putative proteolytic substrate hepatocyte growth factor. Consistent with the growing evidence that desmosomal junctions and their constituents play a role in cancer progression, we demonstrated that overexpression of hepsin promotes ovarian tumor growth in a mouse model. The ability of ectopic hepsin to induce tumor growth in mice is abrogated by the mutation of 3 critical residues in the catalytic domain, thus implicating the enzymatic activity of hepsin in promoting tumor progression. ' 2008 Wiley-Liss, Inc.Key words: desmosome; hepsin; ovarian cancer; serine protease Hepsin is a type II transmembrane serine protease that was originally cloned from cDNA libraries of human liver and hepatoma cells.1 The human hepsin gene localizes to chromosome 19q11-13.2 and encodes a glycoprotein of 417 amino acids with a predicted molecular mass of 51 kDa. 2,3 Hepsin is likely to be synthesized as a single chain zymogen and cleaved by an unknown enzyme to generate the mature, disulfide-linked 2-chain form. 4 In addition to the catalytic domain, which includes the active site triad residues of His, Asp and Ser, hepsin protein is characterized by a macrophage scavenger receptor-like domain of unknown function, a transmembrane domain and a short cytoplasmic domain.1-7 An alternatively-spliced, nontransmembrane isoform of human hepsin was recently identified. 8 Hepsin is frequently overexpressed in prostate cancers, 9-14 renal cell carcinomas and ovarian cancer. [15][16][17][18] The overexpression of hepsin mRNA was found in 60% of low-grade ovarian tumors and 80% of ovarian carcinomas, 17 whereas it was not expressed in normal ovarian tissues. 15 The biological functions of hepsin in normal tissues and cancers are not well understood. In vitro data implicate hepsin in the maintenance of cell morphology and cell growth, 19 blood coagulation through human factor VII activation 20 and developmental processes. 7 The evidence for these functions remains inconclusive since, aside from a profound hearing loss, 21 hepsin knockout mice develop normally and do not show differences in various measures of blood coagulation compared to wild-type littermates. 22,23In vitro assays using neutralizing antibodies demonstrated that, while hepsin does not play a role in the proliferation of prostate, ovarian and hepatoma cell lines in culture, it plays a role in the invasion of ovarian and prostate cells in transwell-based invasio...

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Section: Resultssupporting

confidence: 91%

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confidence: 99%

Hepsin colocalizes with desmosomes and induces progression of ovarian cancer in a mouse model

Miao

Ergel

et al. 2008

Intl Journal of Cancer

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“…The LDLRA and SRCR domains of TMPRSS3 may be involved in binding with extracellular molecules or the cell surface. The putative peptides encoded by the TMPRSS3b and TMPRSS3c transcripts contain only half of the SRCR domain, whereas the 15 .…”

Section: Division Of Medical Genetics University Of Geneva Medicalmentioning

confidence: 99%

Insertion of β-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness

et al. 2001

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Approximately 50% of childhood deafness is caused by mutations in specific genes. Autosomal recessive loci account for approximately 80% of nonsyndromic genetic deafness 1 . Here we report the identification of a new transmembrane serine protease (TMPRSS3; also known as ECHOS1) expressed in many tissues, including fetal cochlea, which is mutated in the families used to describe both the DFNB10 and DFNB8 loci. An 8-bp deletion and insertion of 18 monomeric (∼68-bp) β-satellite repeat units, normally present in tandem arrays of up to several hundred kilobases on the short arms of acrocentric chromosomes, causes congenital deafness (DFNB10). A mutation in a spliceacceptor site, resulting in a 4-bp insertion in the mRNA and a frameshift, was detected in childhood onset deafness (DFNB8). This is the first description of β-satellite insertion into an active gene resulting in a pathogenic state, and the first description of a protease involved in hearing loss.

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“…The importance of hepsin in vivo, however, remains unclear as homozygous hepsin null mice are phenotypically normal (54). An as yet unexplained phenotype of the hepsin Ϫ/Ϫ mice is a 2-fold higher serum concentration of bone-derived alkaline phosphatase compared with wild type mice (55).…”

Section: Minireview: Type II Transmembrane Serine Proteases 858mentioning

confidence: 99%

Type II Transmembrane Serine Proteases

Hooper¹,

Clements²,

Quigley³

et al. 2001

Journal of Biological Chemistry

318

135

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Complete nucleotide sequence, origin of isoform and functional characterization of the mouse hepsin gene

Cited by 13 publications

References 39 publications

Hepsin colocalizes with desmosomes and induces progression of ovarian cancer in a mouse model

Hepsin colocalizes with desmosomes and induces progression of ovarian cancer in a mouse model

Insertion of β-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness

Type II Transmembrane Serine Proteases

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