Disease relevance of ST14

• Our results also suggested that ST14 and TMEFF1 were co-expressed in the human breast cancer cell line MCF7, human placenta, kidney, and liver tissues [1].
• Effect of SNC19/ST14 gene overexpression on invasion of colorectal cancer cells [2].
• The substrate specificity of MT-SP1 was determined using a positional scanning-synthetic combinatorial library and substrate phage techniques [3].
• Since HGF/SF is a well-known extracellular signal, which plays a key role in the control of invasive growth, we investigated the effects of matriptase inhibition in cell lines derived from colon (DLD-1) or prostate (PC-3) carcinomas [4].
• The expression of SNC19/matriptase had no relationship with stages and lymph node metastasis (P>0.05) [5].
• ST14 hypomorphic mice developed hyperproliferative and retention ichthyosis with impaired desquamation, hypotrichosis with brittle, thin, uneven, and sparse hair, and tooth defects [6].

High impact information on ST14

• Overexpression of the type II transmembrane serine protease matriptase is a highly consistent feature of human epithelial tumors [7].
• Modest orthotopic overexpression of matriptase in the skin of transgenic mice caused spontaneous squamous cell carcinoma and dramatically potentiated carcinogen-induced tumor formation [7].
• Matriptase-induced malignant conversion was preceded by progressive interfollicular hyperplasia, dysplasia, follicular transdifferentiation, fibrosis, and dermal inflammation [7].
• Recombination within DXS52 (ST14) locus in family with haemophilia A [8].
• The adaptability of the scaffold was demonstrated by the isolation of inhibitors to two additional serine proteases, MT-SP1/matriptase and Factor XIIa [9].

Chemical compound and disease context of ST14

• In contrast, S1P treatment of breast cancer cells does not activate matriptase, and instead these cells constitutively activate the protease [10].
• Matriptase, a trypsin-like serine protease with two potential regulatory modules (low density lipoprotein receptor and complement C1r/s domains), was initially purified from T-47D breast cancer cells [11].
• In addition, matriptase and its complexes were detected in milk-derived, SV40 T-antigen-immortalized mammary luminal epithelial cell lines, but not in human foreskin fibroblasts or in HT-1080 fibrosarcoma cells [11].
• Matriptase activation and shedding with HAI-1 is induced by steroid sex hormones in human prostate cancer cells, but not in breast cancer cells [12].
• Treatment of cells with 17beta-estradiol had no effect on activation of matriptase in hormone-starved breast cancer cells, in part due to their high constitutive level of activated matriptase [12].

Biological context of ST14

• Quantitative real time PCR revealed that the expression of the TMEFF1 gene was dependent on the transfection of the ST14 gene in the RKO cell line [1].
• In addition, the expression levels of SPINT1, ST14, HGF, and MET mRNAs in the villous tree increased over the course of gestation [13].
• RESULTS: SNC19/ST14 gene overexpression could enhance invasion of colorectal cancer cells in vitro significantly and influence early cell adherence to ECM, but could not change cell movement significantly [2].
• Recombination between the four loci 52A, F9, fragile X, and ST14 is significantly decreased in meioses giving rise to the affected grandsons of normal transmitting males, when compared to families where there are no apparent normal transmitting males [14].
• In 54 informative meioses, three recombinations between the factor VIII locus and the DX13 and/or ST14 loci were observed, giving a recombination rate of 5.5% [15].

Anatomical context of ST14

• The ability of MT-SP1 to activate PARs was assessed by exposing PAR-expressing Xenopus oocytes to the soluble MT-SP1 protease domain [3].
• Matriptase is a type II transmembrane serine protease expressed in most human epithelia, where it is coexpressed with its cognate transmembrane inhibitor, hepatocyte growth factor activator inhibitor (HAI)-1 [16].
• Matriptase has an essential physiological role in profilaggrin processing, corneocyte maturation, and lipid matrix formation associated with terminal differentiation of the oral epithelium and the epidermis, and is also critical for hair follicle growth [16].
• We examined the regulation of activation of matriptase in human breast cancer cells, in comparison to non-transformed mammary epithelial cells 184A1N4 and MCF-10A [10].
• Expression of serine protease SNC19/matriptase and its inhibitor hepatocyte growth factor activator inhibitor type 1 in normal and malignant tissues of gastrointestinal tract [5].

Associations of ST14 with chemical compounds

• ST14 (suppression of tumorigenicity 14) is a transmembrane serine protease that contains a serine protease catalytic (SP) domain, an SEA domain, two complement subcomponent C1r/s (CUB) domains, and four low density lipoprotein receptor class A domains [1].
• However, up to five-fold higher levels of activated matriptase were detected in the conditioned media from the cancer cells grown in the absence of serum and S1P, when compared to non-transformed mammary epithelial cells [10].
• Prometastatic effect of N-acetylglucosaminyltransferase V is due to modification and stabilization of active matriptase by adding beta 1-6 GlcNAc branching [17].
• Sphingosine 1-phosphate, present in serum-derived lipoproteins, activates matriptase [18].
• We further demonstrated that matriptase can convert hepatocyte growth factor/scattering factor to its active form, which can induce scatter of Madin-Darby canine kidney epithelial cells and can activate c-Met tyrosine phosphorylation in A549 human lung carcinoma cells [19].

Physical interactions of ST14

• Finally, homology modeling studies suggested that TMEFF1 might form a complex with ST14 by an interaction between epidermal growth factor and CUB domains [1].
• Indeed, all activated matriptase was detected in complexes with HAI-1 only 5 min after suramin stimulation [20].

Enzymatic interactions of ST14

• When the membrane fraction was separated by SDS/PAGE, the IGFBP-rP1-cleaving activity comigrated with matriptase [21].

Regulatory relationships of ST14

• METHODS AND RESULTS: In endothelial cells, recombinant MT-SP1/matriptase dose-dependently induced interleukin (IL)-8 and IL-6 mRNA and protein expression dependent on its proteolytic activity [22].
• Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates [3].
• However, none of the breast cancer cell lines tested that express the mesenchymal marker vimentin express matriptase or HAI-1, consistent with an epithelial-selective expression of this system [23].
• Taken together, these results support multiple roles for HAI-1 to regulate matriptase, including its proper expression, intracellular trafficking, activation, and inhibition [24].
• The type II transmembrane multidomain serine proteinase MT-SP1/matriptase is highly expressed in many human cancer-derived cell lines and has been implicated in extracellular matrix re-modeling, tumor growth, and metastasis [25].

Other interactions of ST14

• Both are Kunitz-type serine proteinase inhibitors and inhibit not only HGFA but also other serine proteinases, such as membrane-type serine protease 1 (matriptase), plasmin, trypsin and kallikreins [26].
• CONCLUSION: MT-SP1/matriptase induces release of proinflammatory cytokines in endothelial cells through activation of PAR-2 [22].
• Protease-activated receptor 2 (PAR2) and single-chain urokinase-type plasminogen activator are proteins that are localized to the extracellular surface and contain the preferred MT-SP1 cleavage sequence [3].
• Interestingly, these two genes were co-up-regulated in kidney tumors versus normal tissues, consistent with our results that showed the dependence of TMEFF1 expression on ST14 in RKO cells [1].
• Previous studies have shown linkage between the X linked form of the disease and the Xq28 probes ST14, DX13, and F8C [27].

Analytical, diagnostic and therapeutic context of ST14

• The same effect was observed after treatment of these cells with matriptase inhibitors of the 3-amidinophenylalanine-type, CJ-697 or CJ-730 [4].
• In human atherectomies, MT-SP1/matriptase was expressed in blood cells adherent to the endothelium [22].
• Expression of matriptase, as determined by Western blot analysis, was observed in primary human breast, gynecological, and colon carcinomas, but not in stromal-derived ovarian tumors and human sarcomas of various origins and histological grades [23].
• The epithelial-selective expression of matriptase and HAI-1 was further confirmed in human breast cancers by immunohistochemistry and in situ hybridization, where the expression of the protease and the inhibitor were found in the carcinoma cells and in surrounding normal breast epithelia [23].
• Northern blotting shows broad expression of MT-SP1 in a variety of epithelial tissues with high levels of expression in the human gastrointestinal tract and the prostate [28].

References