Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line

Tong, Zhenyue; Illek, Beate; Bhagwandin, Vikash; Verghese, George M.; Caughey, George H.

doi:10.1152/ajplung.00160.2004

Cited by 67 publications

(61 citation statements)

References 37 publications

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“…1A, prostasin migrates as 37-and 40-kDa bands in the apical secretions; however, no prostasin was observed in the basolateral secretions. These results are consistent with previous reports of prostasin secretion from human prostate tissue (48) and from various immortalized mouse cell lines (36,45) but differ from a study in the immortalized bronchial epithelial cell line JME/CF15, in which prostasin was not present in the secretions (43). To clarify whether prostasin is secreted in the airway, we also performed Western blotting on sputum from a CF patient (Fig.…”

Section: Prostasin Is Expressed In a Nonpolarized Distribution But Onsupporting

confidence: 91%

“…Donaldson et al (13) demonstrated that prostasin is expressed in airway epithelium and increases the Na ϩ current by ϳ75% when coexpressed with ENaC in Xenopus oocytes. Furthermore, Tong et al (43) reported an ϳ75% reduction in the Na ϩ conductance of an immortalized airway epithelial cell line following small interference (si)RNAmediated prostasin knockdown. Recent evidence from Bruns et al (4) demonstrated that prostasin cleaves the extracellular loop of the ␥ENaC subunit and thereby increases the open probability of the channel.…”

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confidence: 99%

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Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Myerburg

McKenna²,

Luke³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Airway surface liquid (ASL) absorption is initiated by Na+ entry via epithelial Na+ channels (ENaC), which establishes an osmotic gradient that drives fluid from the luminal to serosal airway surface. We and others have recently reported that a protease/anti-protease balance regulates ENaC in human airway epithelial cells (HAEC) and provides a mechanism for autoregulation of ASL volume. In cystic fibrosis (CF), this balance is disturbed, leading to constitutive proteolytic activation of ENaC and the pathological Na+ hyperabsorption characteristic of this airway disease. Prostasin is a glycosylphosphatidylinositol-anchored serine protease that activates ENaC and is expressed on the surface epithelium lining the airway. In this report we present evidence that prostasin expression is regulated by the ASL volume, allowing for increased proteolytic activation of ENaC when the ASL volume is high. Prostasin activity is further regulated by the cognate serpin protease nexin-1 (PN-1), which is expressed in HAEC and inhibits Na+ absorption by forming an inactive complex with prostasin and preventing the proteolytic processing of prostasin. Whereas these mechanisms regulate prostasin expression in response to ASL volume in non-CF epithelia, HAEC cultured from CF patients express >50% more prostasin on the epithelial surface. These findings suggest that a proteolytic cascade involving prostasin, an upstream prostasin-activating protease, and PN-1 regulate Na+ absorption in the airway and that abnormal prostasin expression contributes to excessive proteolytic activation of ENaC in CF patients.

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Section: Prostasin Is Expressed In a Nonpolarized Distribution But Onsupporting

confidence: 91%

mentioning

confidence: 99%

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Myerburg

McKenna²,

Luke³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The physiological function of Testisin is still not clear. In the case of prostasin, one role that has been identified is the regulation of epithelial Na þ channel (ENaC) function that is critical for normal salt and water balance (Vuagniaux et al, 2000;Tong et al, 2004).…”

mentioning

confidence: 99%

Hypermethylation of the 5′ CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis

et al. 2005

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The Testisin gene (PRSS21) encodes a glycosylphosphatidylinositol (GPI)-linked serine protease that exhibits testis tissue-specific expression. Loss of Testisin has been implicated in testicular tumorigenesis, but its role in testis biology and tumorigenesis is not known. Here we have investigated the role of CpG methylation in Testisin gene inactivation and tested the hypothesis that Testisin may act as a tumour suppressor for testicular tumorigenesis. Using sequence analysis of bisulphite-treated genomic DNA, we find a strong relationship between hypermethylation of a 385 bp 5 0 CpG rich island of the Testisin gene, and silencing of the Testisin gene in a range of human tumour cell lines and in 100% (eight/eight) of testicular germ cell tumours. We show that treatment of Testisinnegative cell lines with demethylating agents and/or a histone deacetylase inhibitor results in reactivation of Testisin gene expression, implicating hypermethylation in Testisin gene silencing. Stable expression of Testisin in the Testisin-negative Tera-2 testicular cancer line suppressed tumorigenicity as revealed by inhibition of both anchorage-dependent cell growth and tumour formation in an SCID mouse model of testicular tumorigenesis. Together, these data show that loss of Testisin is caused, at least in part, by DNA hypermethylation and histone deacetylation, and suggest a tumour suppressor role for Testisin in testicular tumorigenesis.

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“…In addition, the serine protease inhibitor aprotinin reduces the transepithelial sodium transport in an amphibian kidney cell line. In airway epithelial cell lines, elastase, another serine protease, activates ENaC, and a decrease in the expression of prostasin reduces the amiloride-sensitive Na ϩ current (70,71). Clearly, the Po of ENaC is increased by extracellular proteases, an effect on the channel that is independent of changes in intracellular Ca 2ϩ or activation of G protein-coupled receptors (72,73).…”

Section: Modulatory Sites Of Enac Activitymentioning

confidence: 99%

Functional Domains of the Epithelial Sodium Channel

Loffing

Schild

2005

Journal of the American Society of Nephrology

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Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line

Abstract: . Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line.

Cited by 67 publications

References 37 publications

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

Hypermethylation of the 5′ CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis

Functional Domains of the Epithelial Sodium Channel

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