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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review PRSS8 (protease, serine, 8) Li-Mei Chen, Karl X Chai Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL 32816, USA (LMC, KXC) Published in Atlas Database: April 2012 Online updated version : http://AtlasGeneticsOncology.org/Genes/PRSS8ID41880ch16p11.html DOI: 10.4267/2042/47537 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Transcription Identity Description: The full-length human prostasin mRNA, as deduced from a cloned cDNA, contains a 1032nucleotide (nt) open-reading frame that can be translated into 343 AA, a 138-nt 5'-UTR, and a 572-nt 3'-UTR (Yu et al., 1995). Expression: In humans, prostasin mRNA expression was detected by reverse-transcription coupled polymerase chain reaction (RT-PCR) in the total RNA of the prostate, liver, salivary gland, kidney, lung, pancreas, colon, bronchus, and renal proximal tubular cells (Yu et al., 1995). In the human prostate, the prostasin mRNA was localized to the epithelial cells. The urinary bladder epithelial (urothelial) cells of the human and the mouse express the prostasin mRNA and the translated protein (Chen et al., 2009b; Chen et al., 2006a). Human breast epithelial cells also express the prostasin mRNA and the translated protein (Chen and Chai, 2002; Bergum et al., 2012). Prostasin mRNA is expressed in the rhesus monkey endometrial glandular epithelium on Day 12 and Day 18 of pregnancy, and in the placental villi, trophoblastic column, trophoblastic shell, and the fetal-maternal border on Day 18 and Day 26 (Lin et al., 2006). The endometrial prostasin expression subsides but the placental expression increases further along the gestational course. Expression regulation: In the mouse renal cortical collecting duct M-1 cells prostasin mRNA expression can be up-regulated by aldosterone treatment, which is also a mechanism of increasing urinary prostasin excretion in rats following whole-animal infusion (Narikiyo et al., 2002). Aldosterone infusion was shown to induce prostasin mRNA expression in the left colon of the rat as well (Fukushima et al., 2004). Prostasin mRNA (and protein) expression in the M-1 cells can be repressed by transforming growth factor Other names: CAP1, PROSTASIN HGNC (Hugo): PRSS8 Location: 16p11.2 Local order: Centromere to telomere. DNA/RNA Description The human prostasin/PRSS8 gene consists of six (6) exons and five (5) introns. A 7-Kb (kilobase) genomic region containing the human prostasin/PRSS8 gene was fully sequenced in the original cloning report (Yu et al., 1996), with a 1.4-kb 5'-flanking region and a 1.2-kb 3'flanking region. A single chromosomal location at 16p11.2 was reported to harbor the human prostasin/PRSS8 gene. The mouse orthologue of the prostasin/prss8 gene, located on Chromosome 7, is highly homologous to the human prostasin/PRSS8 gene, with a six-exon organization (Verghese et al., 2004). The mouse prostasin/prss8 gene's 3'-untranslated region (UTR) overlaps with the 3'-UTR of the Myst1 histone acetyltransferase gene. Genetic mapping evidence provided support for the rat 'fuzzy' and 'hairless' mutations to be orthologues of the mouse 'frizzy' mutation (Ahearn et al., 2002). A T/A transversion missense mutation, changing a Val to an Asp at amino acid (AA) residue 170 of the mouse prostasin, was shown to be causative to the mutant 'frizzy' phenotype (Spacek et al., 2010). The 'hairless' rat has a 12-bp (base pair) deletion in the third exon of the prss8 gene's coding region, whereas the 'fuzzy' rat does not have any prss8 coding sequence changes. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9) 658 PRSS8 (protease, serine, 8) Chen LM, Chai KX beta-1 (TGF-b1), via down-regulating the NF-kB signalling (Tuyen et al., 2005). In the mouse urinary bladder, prostasin mRNA expression is down-regulated in association with inflammation caused by intraperitoneal injection of bacterial lipopolysaccharides (LPS) (Chen et al., 2006a). Promoter DNA hypermethylation and histone deacetylation are epigenetic mechanisms that downregulate prostasin mRNA transcription in human breast and prostate cancer cell lines (Chen and Chai, 2002; Chen et al., 2004). Nerve growth factor (NGF) induces prostasin mRNA expression in human prostate cancer cell lines (DU-145 and PC-3) with epigenetically repressed prostasin expression (Chen et al., 2004). The sterol regulatory element-binding proteins (SREBPs) SREBP-1c and SREBP-2 are positive transcriptional regulators of prostasin expression in human epithelial cell lines (Chen et al., 2006b), and the binding sites of SREBP-2 in the human prostasin/PRSS8 gene promoter region have been determined (Chen et al., 2006c). The SNAIL family zinc-finger transcription factors SNAIL and SLUG are negative regulators of prostasin transcription in human epithelial cell lines (Chen et al., 2006b). The SREBPs and SLUG are responsive to dihydrotestosterone (DHT) with up-regulation of expression and thus making the prostasin/PRSS8 gene indirectly responsive to androgen regulation (Chen et al., 2006b). Localisation A glycosylphosphatidylinositol (GPI) anchor tethers the mature prostasin protein to the plasma membrane (Chen et al., 2001b). The mature prostasin protein can be released from the membrane by phosphatidylinositol-specific phospholipase C (Chen et al., 2001b), or GPI-specific phospholipase D1 (Gpld1) (Verghese et al., 2006). But in the kidney shedding of prostasin from the cell membrane may be peptidasedependent (Verghese et al., 2006). In the epithelium proteolytic cleavage of the pro-prostasin by matriptase must occur at the basolateral membrane but transcytosis brings the GPI-anchored prostasin to its major cellular location, the apical membrane (Friis et al., 2011). Function Prostasin was first identified as a serine protease in human seminal fluid, purified by the use of aprotininaffinity chromatography (Yu et al., 1994). This native purified form of human prostasin displayed a trypsinlike proteolytic activity with a pH optimum of 9.0 on some synthetic substrates. The serine protease catalytic triad of the human prostasin was deduced after the cloning of its cDNA, as His53/Asp102/Ser206 (Yu et al., 1995). A Ser206Ala mutant of the human prostasin was used to confirm the serine active site (Chen et al., 2008). Using a recombinant human prostasin catalytic domain (i.e., lacking the GPI anchor and cellular context) produced in insect cells, the substrate specificity at the P1 position was determined to be either Arg or Lys (Shipway et al., 2004). The S1 substrate subsite loop of human prostasin was found to bind divalent ions such as Ca++ in a crystallized form with protease inhibitors, suggesting that divalent cations can regulate the protease activity (Spraggon et al., 2009). Natural substrates: ENaC - The first candidate physiological substrate of prostasin was identified in a Xenopus kidney epithelial cell line (A6) in a functional cloning assay to find proteolytic activators of the epithelial sodium channel (ENaC), thus earning the nickname CAP1 (channel-activating protease 1) for prostasin (Vallet et al., 1997). The rat prostasin, when co-expressed with rat ENaC in Xenopus oocytes produces increased amiloride-sensitive sodium current, indicating ENaC activation by the co-expressed prostasin (Adachi et al., 2001). Activation of ENaC in the Xenopus oocyte requires the GPI-anchorage of the xCAP1 (Xenopus CAP1), indicating an extracellular location for the proteolytic activation of ENaC by xCAP1/prostasin (Vallet et al., 2002). Using a nasal epithelial cell line JMF/CF15 homozygous for the ∆F508 cystic fibrosis mutation, prostasin downregulation by small-interfering RNA (siRNA) was shown to drop ENaC currents by >70% (Tong et al., 2004). Pseudogene No prostasin/PRSS8 pseudogene has been identified to date. Protein Description The mature form of the human prostasin is 40 kDa in size as determined by SDS-PAGE, and has a pI in the range of 4.5-4.8 (Yu et al., 1994). The pro-peptide of the human prostasin is 311 AA in length (Yu et al., 1995), and it is cleaved at Arg12 in the sequence of Gln-Ala-Arg-Ile by matriptase, hepsin, or plasmin (Chen et al., 2010a; Svenningsen et al., 2009) to produce a two-chain (12 AA and 277 AA) disulphidelinked mature protein (Yu et al., 1995). Expression In humans the prostasin protein could be detected by radioimmunoassay (RIA) in tissue extracts of the prostate, colon, lung, kidney, pancreas, salivary gland, liver, and bronchi, as well as in seminal fluid and urine; but not in tissue extracts of the brain, muscle, testis, ventricle, atrium, or aorta (Yu et al., 1994). By immunohistochemistry (IHC), human prostasin has been detected in the epithelial cells of the prostate (Yu et al., 1994; Chen et al., 2001a), the urinary bladder (Chen et al., 2009b), and the breast (Bergum et al., 2012); and the placenta trophoblasts during early pregnancy (Ma et al., 2009). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9) 659 PRSS8 (protease, serine, 8) Chen LM, Chai KX with testisin (Hooper et al., 1999) and gamma tryptase (Caughey et al., 2000). The human prostasin cleaves the gamma subunit of ENaC at RKRK(186) (Carattino et al., 2008). In the mouse however, ENaC activation by mCAP1 (mouse CAP1) does not require its catalytic/proteolytic function, though the GPI anchorage is still required for mCAP1 in this role (Andreasen et al., 2006). Natural substrates: Matriptase - While an activating protease for pro-prostasin, matriptase has also been shown to be a substrate of prostasin in mouse lung fibroblast cells and human keratinocytes with the use of soluble recombinant active human prostasin (Camerer et al., 2010). This mechanism explains the activation of proteaseactivated receptor 2 (PAR-2) upon addition of the soluble active prostasin, which accomplishes the PAR2 activation via activating matriptase, a direct PAR-2 activating protease. This mechanism also helps explain the enhancement of matriptase cleavage of the extracellular domain (ECD) of the epidermal growth factor receptor (EGFR), which was first thought to be potentially cleaved by prostasin as well (Chen et al., 2008), but later proven not to be the case (Chen et al., 2010a). In human prostate epithelial cells however, prostasin also negatively regulate PAR-2 signalling, an action that requires prostasin's serine active site but not its GPI anchor (Chen et al., 2009a). Inhibitors: As a serine protease, the purified form of the human prostasin can be inhibited by aprotinin, antipain, leupeptin, and benzamidine (Yu et al., 1994). In the serpin-class serine protease inhibitors, protease nexin 1 (PN-1) is the cognate serpin for prostasin, forming a covalent complex with the latter to achieve inhibition of its serine protease activity (Chen et al., 2004). In the human PN-1 reactive site, the Leu-Ile-Ala-Arg residues at the P4-P1 positions of this suicide inhibitor should represent also the optimal substrate for prostasin. A Kunitz-type reversible serine protease inhibitor, hepatocyte growth factor activator inhibitor 1 (HAI-1) is a physiologically relevant inhibitor of prostasin (Fan et al., 2005; Chen et al., 2010b), whereas HAI-2 can inhibit the prostasin protease domain in vitro (Shipway et al., 2004). The synthetic serine protease inhibitor camostat mesilate and its active metabolite FOY-251 can inhibit prostasin serine protease activity in vitro (Maekawa et al., 2009), and possibly in vivo as well (Coote et al., 2009). Mutations Germinal In mice, homozygous loss of the prostasin/prss8 gene is embryonically lethal so conditional knockouts are needed for investigating prostasin/prss8 functions in vivo (Rubera et al., 2002). In humans, no Mendelian hereditary conditions on the basis of prostasin/PRSS8 gene mutations have been described to date. A transcribed single nucleotide polymorphism (tSNP) in the human prostasin/PRSS8 gene (rs12597511: C;T) shows genotype association with hypertension (Zhu et al., 2008). A missense SNP, E342K, of the human prostasin/PRSS8 gene has been reported (Li et al., 2011). Another human prostasin/PRSS8 gene SNP, 2827 G>A, was reported to show genotype association with body mass index (BMI), OGTT-2h glucose, IRT3h insulin, and serum potassium (Li et al., 2011). Implicated in Prostate cancer Note Prostasin expression is down-regulated in high-grade prostate cancers, and correspondingly in highly invasive human and mouse prostate cancer cell lines (Chen et al., 2001a). Re-expression of prostasin in highly invasive human prostate cancer cell lines (DU-145 and PC-3) reduced their in vitro invasion. Down-regulated prostasin expression was associated with metastatic and hormone-refractory prostate cancers in a small study involving 54 cases (Takahashi et al., 2003). This study confirmed the inverse correlation of prostasin expression with histological differentiation but failed to find correlations with clinical staging. Another small study (96 cases and 86 controls) suggested that RT-PCR amplification of the prostasin mRNA from circulating tumor cells may be applicable as a method for early diagnosis of prostate cancer cell dissemination (Laribi et al., 2001). Breast cancer Note A coordinated co-expression pattern in human breast cancers has been reported for prostasin and its activating enzyme/substrate matriptase (Bergum et al., 2012). Prostasin expression is down-regulated in highly invasive human breast cancer cells whereas reexpression of prostasin in these cells reduced their in vitro invasion (Chen and Chai, 2002). Homology The human prostasin was shown to share sequence homology at the amino acid level with acrosin, plasma kallikrein, and hepsin upon sequencing of its full-length cDNA (Yu et al., 1995). Prostasin also shares amino acid sequence homology Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9) 660 PRSS8 (protease, serine, 8) Chen LM, Chai KX prostasin in primary aldosteronism patients is significantly increased (Narikiyo et al., 2002). Rats receiving tail-vein injection of adenoviruses carrying a human prostasin transgene expressed the transgene ubiquitously and showed elevated plasma aldosterone and hypertension along with reduced urinary potassium excretion and increased urinary sodium and kallikrein excretion (Wang et al., 2003). Prostasin regulates aldosterone production in human adrenocortical H295R cells by a protease-independent but calcium- and protein kinase C (PKC) dependent mechanism (Ko et al., 2010). Ovarian cancer Note Prostasin is detected by IHC more intensely in the epithelial and stromal cells of cancerous ovarian tissues than those of normal ovarian tissues (Mok et al., 2001). Serum prostasin levels may be applicable as a highly sensitive and specific marker for detecting ovarian cancer. Another study also revealed serum prostasin as a potentially informative marker for ovarian cancer (Yip et al., 2011). Colon cancer Urinary prostasin Note Prostasin mRNA expression was found to be correlated to prolonged survival after surgery in colon cancer patients in a small study (Cavalieri et al., 2007). In tissues from the same colon cancer patients, prostasin mRNA expression was found to be slightly increased in the cancerous sections whereas membrane localization of the prostasin protein in colon cancer tissues appears to be disturbed as well (Selzer-Plon et al., 2009). Note Urinary prostasin level may be applicable as a marker for upstream ENaC activation and this marker is increased in primary aldosteronism patients after volume expansion (Olivieri et al., 2005). Another study also indicated a strong correlation between urinary prostasin levels and urinary or plasma aldosterone levels in hypertensive patients (Koda et al., 2009). Other cancers Cystic fibrosis (CF) Note Prostasin is among five (5) genes that can be used for separating the chromophobe renal cell carcinoma (RCC) from oncocytoma based on their differential mRNA expression in these two tumor types (Rohan et al., 2006). In the human hepatoma cell line HepG2 prostasin mRNA expression can be reduced by poly unsaturated fatty acids (Fujiwara et al., 2003). Note ENaC function related condition. Disease Prostasin was found to be a major regulator of ENaCmediated sodium current in a human epithelial cell line carrying the ∆F508 CF mutation (Tong et al., 2004). In this context, prostasin expression in human airway epithelial cells can be regulated by the airway surface liquid (ASL) volume and CF patients express >50% more prostasin in their airway epithelial cells than nonCF subjects (Myerburg et al., 2008). Inflammation Disease Prostasin expression in the urinary bladder is downregulated by LPS-induced inflammation marked by the characteristic up-regulation of the inducible nitric oxide synthase (iNOS) expression (Chen et al., 2006a). Forced expression of prostasin in the bladder urothelial cells attenuated the iNOS induction. Silencing prostasin expression in the human benign prostatic hyperplasia cell line BPH-1 is associated with up-regulation of iNOS expression as well as that of interleukins 6 and 8 (IL-6 and IL-8) (Chen et al., 2009a). In the mouse kidney cortical collecting duct M-1 cells, treatment with IL-6 was shown to increase prostasin protein expression (Li et al., 2010). Transgenic mice overexpressing prostasin in the skin show skin inflammation and ichthyosis, phenotypes that are not manifested in PAR-2 null mice, indicating a PAR-2 mediated mechanism for prostasin's role in skin inflammation (Frateschi et al., 2011). Epidermal/Epithelial terminal differentiation Disease Mice born with a prostasin/prss8 knockout in the skin die within 60 hours, presenting a phenotype of severely malformed stratum corneum (SC) (Leyvraz et al., 2005). This defect results in impaired skin barrier function manifested as increased skin permeability and dehydration. At the molecular level, occludin is absent among the tight junction (TJ) proteins thus preventing the proper formation of the tight junctions and terminal differentiation of the epidermis. Along the same line of reasoning, the renal collecting duct epithelium requires apically expressed, GPI-anchored, and lipid-raftassociated active prostasin serine protease for establishment of high transepithelial resistance (TER), an indicator of epithelial terminal differentiation (Steensgaard et al., 2010). Aldosteronism and hypertension Note ENaC function related condition. Disease Consistent with aldosterone's transcriptional activator role on prostasin expression, urinary excretion of Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9) References Yu JX, Chao L, Chao J. Prostasin is a novel human serine proteinase from seminal fluid. Purification, tissue distribution, 661 PRSS8 (protease, serine, 8) Chen LM, Chai KX and localization in prostate gland. J Biol Chem. 1994 Jul 22;269(29):18843-8 required for activation of ENaC in the Xenopus oocyte. J Am Soc Nephrol. 2002 Mar;13(3):588-94 Yu JX, Chao L, Chao J. 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