Alternative titles; symbols
HGNC Approved Gene Symbol: ST14
Cytogenetic location: 11q24.3 Genomic coordinates (GRCh38): 11:130,159,782-130,210,362 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q24.3 | Ichthyosis, congenital, autosomal recessive 11 | 602400 | Autosomal recessive | 3 |
ST14 is a serine protease that functions extracellularly as a membrane-bound cell surface protein or as a soluble extracellular protease following release of its ectodomain. ST14 has broad substrate specificity and can cleave growth factors and proteins of the extracellular matrix and coagulation cascade (summary by Kim et al., 2011).
Lin et al. (1999) cloned an ST14 cDNA encoding a protease previously identified in breast cancer cells (Lin et al., 1997). The deduced 683-amino acid protein has a calculated molecular mass of 75.6 kD. It contains an integrin-binding site near the N terminus, 3 potential N-glycosylation sites, 4 tandem repeats homologous to the 35-amino acid cysteine-containing repeats of the LDL receptor, a putative proteolytic activation site, and a C-terminal region with similarity to the trypsin-like serine proteases. Lin et al. (1999) purified ST14 in a 95-kD complex with a 40-kD binding protein identified as SPINT1 (605123), a Kunitz-type serine protease inhibitor. They found that ST14 is secreted from breast cancer cells and localizes at the cell surface.
Takeuchi et al. (1999) independently cloned ST14 as a protease associated with prostate cancer tumor cells, using degenerate primers for a chymotrypsin active site as probe. Sequence analysis showed that ST14 lacks a signal sequence and is likely to be a membrane-associated serine protease. By Northern blot analysis, they identified a 3.3-kb transcript in epithelial tissues including prostate, kidney, lung, small intestine, stomach, colon, and placenta, as well as in spleen, liver, leukocytes, and thymus. No expression was found in muscle, brain, ovary, or testis. Expression was also observed in a colorectal adenocarcinoma cell line, but not in several other cell lines tested. By Northern and Western blot analysis of normal breast and breast cancer cell lines, Oberst et al. (2001) found complete concordance in expression of ST14 and SPINT1; the expression correlated with expression of epithelial cell markers.
Friedrich et al. (2002) expressed the catalytic domain of ST14 and solved its crystal structure in complex with benzamidine at 1.3 angstrom. Their analysis disclosed a (chymo)trypsin-like S1 pocket, a small hydrophobic S2 subsite, and an open negatively charged S4 cavity that favors the binding of basic P3/P4 residues. They noted that the specificity of ST14 differs substantially from that of trypsin in that it requires recognition of additional residues surrounding the scissile peptide bond.
Zhang et al. (1998) mapped the ST14 gene to chromosome 11q24-q25 by fluorescence in situ hybridization. They noted that colorectal, breast, and ovarian carcinomas frequently show loss of heterozygosity at this site.
Gross (2015) mapped the ST14 gene to chromosome 11q24.3 based on an alignment of the ST14 sequence (GenBank AB030036) with the genomic sequence (GRCh38).
Kim et al. (2011) found that mouse epithin cleaved Tie2 (TEK; 600221), a receptor tyrosine kinase with a role in endothelial vessel remodeling and stability. Immunoprecipitation analysis revealed that interaction of epithin and Tie2 required phorbol ester-mediated cell activation. Tie2 was predominantly expressed in endothelial cells, while epithin was often expressed on the surface of surrounding cells, including epithelial cells. Coculture experiments revealed that epithin expressed on mouse thymic epithelial cells could cleave Tie2 expressed on endothelial cells. Soluble epithin released to the culture medium did not cleave Tie2. Epithin-mediated Tie2 cleavage induced phosphorylation and activation of the truncated Tie2 protein independent of the Tie2 ligand angiopoietin-1 (ANGPT1; 601667), resulting in downstream Tie2 signaling via the p85 subunit of PI3 kinase (PIK3R1; 171833). Knockdown of epithin reduced the ability of mouse epithelial cells to migrate through a confluent endothelial cell monolayer and reduced metastasis of mouse mammary tumor cells in vivo. Kim et al. (2011) concluded that epithin expressed on tumor cell surfaces can generate a pathway for metastasis directly by breaking down endothelial cell junctions via TIE2 cleavage and indirectly via activation of truncated TIE2, leading to downstream remodeling of the endothelial cell cytoskeleton and cell retraction.
Basel-Vanagaite et al. (2007) described a novel autosomal recessive ichthyosis with hypotrichosis syndrome (ARCI11; 602400) characterized by congenital ichthyosis associated with abnormal hair. Using homozygosity mapping, they mapped the disease locus to 11q24.3-q25. Mutation analysis revealed a missense mutation, G827R (606797.0001), in the highly conserved peptidase S1-S6 domain. Affected individuals showed marked skin hypokeratosis due to impaired degradation of the stratum corneum corneodesmosomes, which suggested that matriptase plays a significant role in epidermal desquamation.
In a 2.5-year-old girl with ARCI11, Avrahami et al. (2008) identified a homozygous mutation in the ST14 gene (M1I; 606797.0002).
In a large Emirati Bedouin pedigree and a Turkish woman with ichthyosis, hypotrichosis, and follicular atrophoderma mapping to chromosome 11q24, Alef et al. (2009) analyzed the candidate gene ST14 and identified homozygosity for a splice site mutation (606797.0003) and a 1-bp deletion (606797.0004), respectively. Differentiated patient keratinocytes showed loss of matriptase, reduced proteolytic activation of prostasin (600823), and disturbed processing of profilaggrin (see 135940).
Matriptase knockout mice (List et al. (2002, 2006)) die shortly after birth as a result of deficient epidermal barrier function in newborn skin. They also demonstrate abnormal hair follicle development and disturbed thymic homeostasis that results in increased lymphocyte apoptosis in the thymus of newborn mice. Transplantation of skin from matriptase-null knockout mice onto adult athymic nude mice resulted in severe epidermal thickening, the formation of ichthyosis-like epidermal scales, and almost complete absence of erupted pelage hairs (List et al., 2003).
Szabo et al. (2009) found that Spint -/- mice had severe growth retardation and did not survive beyond postnatal day 16. Spint1 -/- mice presented histologically with overt hyperkeratosis of the forestomach, hyperkeratosis and acanthosis of the epidermis, and hypotrichosis associated with abnormal cuticle development. Significant suppression of matriptase via a hypomorphic mutation in the St14 gene, to avoid lethality caused by complete loss of matriptase, reversed the phenotype of Spint1 -/- mice. Spint -/- St14 -/hypomorphic mice gained weight at near normal rates, had unaltered long-term survival, were outwardly healthy, and were histologically unremarkable. Spint -/- St14 -/hypomorphic mice were only distinguished from St14 -/hypomorphic mice by reduced accumulation of body fat.
In Spink5 (605010) -/- mouse model, Sales et al. (2010) demonstrated that matriptase initiated Netherton syndrome (256500) by premature activation of a pro-kallikrein (see 147910) cascade. Autoactivation of proinflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from Spink5 -/- mice dampened inflammation, eliminated aberrant protease activity, prevented detachment of the stratum corneum, and improved the barrier function of the epidermis.
In all 3 affected members of a consanguineous Israeli Arab family segregating autosomal recessive congenital ichthyosis with hypotrichosis (ARCI11; 602400), Basel-Vanagaite et al. (2007) identified a 2672G-A transition in exon 19 of the ST14 gene, resulting in a gly827-to-arg (G827R) substitution in the peptidase S1-S6 domain.
Desilets et al. (2008) studied the biochemical and functional consequences of the G837R mutation, located within the catalytic domain of the matriptase enzyme. Expressed in E. coli, the mutant zymogen did not undergo autocatalytic cleavage to its active form as did wildtype matriptase. Direct measurement of enzymatic activity showed proteolytic activity with wildtype matriptase, but not with the G827R mutant, which remained inactive despite 24 hours of dialysis. Proteolytic activity measured in transfected HEK293 cells confirmed that wildtype matriptase was active and that the G827R mutation completely abolished its catalytic activity in mammalian cells.
In a 2.5-year-old girl with congenital ichthyosis and hypotrichosis (ARCI11; 602400), Avrahami et al. (2008) identified a homozygous 3G-A transition in exon 1 of the ST14 gene, resulting in a met1-to-ile (M1I) substitution. If protein translation were to start at the second methionine, the predicted protein would lack the first 93 residues of the 855-residue protein. The mutation was not found in 236 control chromosomes.
In 5 affected sibs from a consanguineous Emirati Bedouin family segregating congenital ichthyosis and hypotrichosis with follicular atrophoderma (ARCI11; 602400), originally reported by Lestringant et al. (1998), Alef et al. (2009) identified homozygosity for a c.2269+1G-A transition in intron 17 of the ST14 gene that segregated with disease in the family. Minigene assay in HEK293 cells revealed several splice products, all predicted to result in premature stop codons, with Val727AlafsTer5 being the major mutant peptide.
In a Turkish woman from a multiply consanguineous family with ichthyosis and hypotrichosis with follicular atrophoderma (ARCI11; 602400), originally reported by Tursen et al. (2002), Alef et al. (2009) identified homozygosity for a 1-bp deletion (c.2034delG) in the ST14 gene, predicted to result in a premature termination codon after 84 residues (Leu678PhefsTer84). Matriptase was completely absent from patient keratinocytes and only unprocessed prostasin (600823) was present. In addition, although profilaggrin (see 135940) was almost undetectable in differentiated keratinocytes from control individuals, there was a massive signal of profilaggrin in patient keratinocytes, with a clearly reduced amount of filaggrin monomers compared to normal keratinocytes.
Alef, T., Torres, S., Hausser, I., Metze, D., Tursen, U., Lestringant, G. G., Hennies, H. C. Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing. J. Invest. Derm. 129: 862-869, 2009. [PubMed: 18843291] [Full Text: https://doi.org/10.1038/jid.2008.311]
Avrahami, L., Maas, S., Pasmanik-Chor, M., Rainshtein, L., Magal, N., Smitt, J. H. S., van Marle, J., Shohat, M., Basel-Vanagaite, L. Autosomal recessive ichthyosis with hypotrichosis syndrome: further delineation of the phenotype. Clin. Genet. 74: 47-53, 2008. [PubMed: 18445049] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01006.x]
Basel-Vanagaite, L., Attia, R., Ishida-Yamamoto, A., Rainshtein, L., Ben Amitai, D., Lurie, R., Pasmanik-Chor, M., Indelman, M., Zvulunov, A., Saban, S., Magal, N., Sprecher, E., Shohat, M. Autosomal recessive ichthyosis with hypotrichosis caused by a mutation in ST14, encoding type II transmembrane serine protease matriptase. Am. J. Hum. Genet. 80: 467-477, 2007. [PubMed: 17273967] [Full Text: https://doi.org/10.1086/512487]
Desilets, A., Beliveau, F., Vandal, G., McDuff, F. O., Lavigne, P., Leduc, R. Mutation G827R in matriptase causing autosomal recessive ichthyosis with hypotrichosis yields an inactive protease. J. Biol. Chem. 283: 10535-10542, 2008. [PubMed: 18263585] [Full Text: https://doi.org/10.1074/jbc.M707012200]
Friedrich, R., Fuentes-Prior, P., Ong, E., Coombs, G., Hunter, M., Oehler, R., Pierson, D., Gonzalez, R., Huber, R., Bode, W., Madison, E. L. Catalytic domain structures of MT-SP1/matriptase, a matrix- degrading transmembrane serine proteinase. J. Biol. Chem. 277: 2160-2168, 2002. [PubMed: 11696548] [Full Text: https://doi.org/10.1074/jbc.M109830200]
Gross, M. B. Personal Communication. Baltimore, Md. 12/28/2015.
Kim, C., Lee, H. S., Lee, D., Lee, S. D., Cho, E.-G., Yang, S. J., Kim, S. B., Park, D., Kim, M. G. Epithin/PRSS14 proteolytically regulates angiopoietin receptor Tie2 during transendothelial migration. Blood 117: 1415-1424, 2011. [PubMed: 21097670] [Full Text: https://doi.org/10.1182/blood-2010-03-275289]
Lestringant, G. G., Kuster, W., Frossard, P. M., Happle, R. Congenital ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis: a new genodermatosis? Am. J. Med. Genet. 75: 186-189, 1998. [PubMed: 9450882] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980113)75:2<186::aid-ajmg12>3.0.co;2-l]
Lin, C.-Y., Anders, J., Johnson, M., Sang, Q. A., Dickson, R. B. Molecular cloning of cDNA for matriptase, a matrix-degrading serine protease with trypsin-like activity. J. Biol. Chem. 274: 18231-18236, 1999. [PubMed: 10373424] [Full Text: https://doi.org/10.1074/jbc.274.26.18231]
Lin, C.-Y., Wang, J.-K., Torri, J., Dou, L., Sang, Q. A., Dickson, R. B. Characterization of a novel, membrane-bound, 80-kDa matrix-degrading protease from human breast cancer cells: monoclonal antibody production, isolation, and localization. J. Biol. Chem. 272: 9147-9152, 1997. [PubMed: 9083044]
List, K., Bugge, T. H., Szabo, R. Matriptase: potent proteolysis on the cell surface. Molec. Med. 12: 1-7, 2006. [PubMed: 16838070] [Full Text: https://doi.org/10.2119/2006-00022.List]
List, K., Haudenschild, C. C., Szabo, R., Chen, W., Wahl, S. M., Swaim, W., Engelholm, L. H., Behrendt, N., Bugge, T. H. Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis. Oncogene 21: 3765-3779, 2002. [PubMed: 12032844] [Full Text: https://doi.org/10.1038/sj.onc.1205502]
List, K., Szabo, R., Wertz, P. W., Segre, J., Haudenschild, C. C., Kim, S.-Y., Bugge, T. H. Loss of proteolytically processed filaggrin caused by epidermal deletion of matriptase/MT-SP1. J. Cell Biol. 163: 901-910, 2003. [PubMed: 14638864] [Full Text: https://doi.org/10.1083/jcb.200304161]
Oberst, M., Anders, J., Xie, B., Singh, B., Ossandon, M., Johnson, M., Dickson, R. B., Lin, C.-Y. Matriptase and HAI-1 are expressed by normal and malignant epithelial cells in vitro and in vivo. Am. J. Path. 158: 1301-1311, 2001. [PubMed: 11290548] [Full Text: https://doi.org/10.1016/S0002-9440(10)64081-3]
Sales, K. U., Masedunskas, A., Bey, A. L., Rasmussen, A. L., Weigert, R., List, K., Szabo, R., Overbeek, P. A., Bugge, T. H. Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nature Genet. 42: 676-683, 2010. [PubMed: 20657595] [Full Text: https://doi.org/10.1038/ng.629]
Szabo, R., Kosa, P., List, K., Bugge, T. H. Loss of matriptase suppression underlies Spint1 mutation-associated ichthyosis and postnatal lethality. Am. J. Path. 174: 2015-2022, 2009. [PubMed: 19389929] [Full Text: https://doi.org/10.2353/ajpath.2009.090053]
Takeuchi, T., Shuman, M. A., Craik, C. S. Reverse biochemistry: use of macromolecular protease inhibitors to dissect complex biological processes and identify a membrane-type serine protease in epithelial cancer and normal tissue. Proc. Nat. Acad. Sci. 96: 11054-11061, 1999. [PubMed: 10500122] [Full Text: https://doi.org/10.1073/pnas.96.20.11054]
Tursen, U., Kaya, T. I., Ikizoglu, G., Aktekin, M., Aras, N. Genetic syndrome with ichthyosis: congenital ichthyosis, follicular atrophoderma, hypotrichosis, and woolly hair; second report. Brit. J. Derm. 147: 604-631, 2002. [PubMed: 12207612] [Full Text: https://doi.org/10.1046/j.1365-2133.2002.48461.x]
Zhang, Y., Cai, X., Schlegelberger, B., Zheng, S. Assignment of human putative tumor suppressor genes ST13 (alias SNC6) and ST14 (alias SNC19) to human chromosome bands 22q13 and 11q24-q25 by in situ hybridization. Cytogenet. Cell Genet. 83: 56-57, 1998. [PubMed: 9925927] [Full Text: https://doi.org/10.1159/000015125]