Cloning and functional characterization of human sodium-dependent organic anion transporter (SLC10A6).
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Human SOAT expressed in HEK293 cells mediates sodium-dependent uptake of DHEA sulfate, estrone-3-sulfate and pregnenolone sulfate with low-micromolar affinity.
"We established a stable SOAT-HEK293 cell line that showed sodium-dependent transport of dehydroepiandrosterone sulfate, estrone-3-sulfate, and pregnenolone sulfate with apparent K(m) values of 28.7, 12.0, and 11.3 microm, respectively."
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Unconjugated and taurine-conjugated trihydroxy/dihydroxy bile acids are not SOAT substrates, whereas the sulfoconjugated bile acid taurolithocholic acid-3-sulfate is transported sodium-dependently.
"Although bile acids, such as taurocholic acid, cholic acid, and chenodeoxycholic acid, were not substrates of SOAT, the sulfoconjugated bile acid taurolithocholic acid-3-sulfate was transported by SOAT-HEK293 cells in a sodium-dependent manner"
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SOAT is most highly expressed in testis, then placenta and pancreas.
"SOAT mRNA is most highly expressed in testis. Relatively high SOAT expression was also detected in placenta and pancreas."
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SOAT is a close paralog of the bile acid carriers ASBT and NTCP.
"SOAT shows 42% sequence identity to the ileal apical sodium-dependent bile acid transporter ASBT and 33% sequence identity to the hepatic Na(+)/taurocholate-cotransporting polypeptide NTCP."
Membrane transporters for sulfated steroids in the human testis--cellular localization, expression pattern and functional analysis.
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LC-MS/MS profiling of cell lysates confirms inward-directed SOAT transport of DHEAS and estrone-3-sulfate and identifies beta-estradiol-3-sulfate and androstenediol-3-sulfate as new substrates.
"With this technique, the cellular inward-directed SOAT transport was verified for the established substrates dehydroepiandrosterone sulfate and estrone-3-sulfate."
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beta-Estradiol-3-sulfate and androstenediol-3-sulfate are SOAT substrates.
"Additionally, β-estradiol-3-sulfate and androstenediol-3-sulfate were identified as novel SOAT substrates."
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SOAT mRNA is reduced in testis biopsies showing hypospermatogenesis.
"Only SOAT was significantly lower expressed in biopsies showing hypospermatogenesis."
Transport of the placental estriol precursor 16α-hydroxy-dehydroepiandrosterone sulfate (16α-OH-DHEAS) by stably transfected OAT4-, SOAT-, and NTCP-HEK293 cells.
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SOAT transports the estriol precursor 16alpha-OH-DHEAS strictly sodium-dependently, with low affinity (Km 319 uM) but high capacity.
"stably transfected SOAT- and NTCP-HEK293 cells showed uptake only under sodium conditions with Km of 319.0 ± 59.5 μM and Vmax of 1465.8 ± 118.8 pmol/mg protein/min for SOAT"
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SOAT protein is located in the apical membrane of human placental syncytiotrophoblasts and in vessel endothelium.
"Immunohistochemical studies and in situ hybridization of formalin fixed and paraffin embedded sections of human late term placenta showed expression of SOAT in syncytiotrophoblasts, predominantly at the apical membrane as well as in the vessel endothelium."
Transport of steroid 3-sulfates and steroid 17-sulfates by the sodium-dependent organic anion transporter SOAT (SLC10A6).
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SOAT shows highly specific transport activity for sulfated steroids.
"The sodium-dependent organic anion transporter SOAT/Soat shows highly specific transport activity for sulfated steroids."
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SOAT substrate recognition requires a planar lipophilic steroid backbone and a single negatively charged sulfate group at position 3' or 17'; a second sulfate abolishes transport.
"SOAT substrates from the group of sulfated steroids are characterized by a planar and lipophilic steroid backbone in trans-trans-trans conformation of the rings and a negatively charged mono-sulfate group at positions 3' or 17' with flexibility for α- or β- orientation."
Substrate Specificities and Inhibition Pattern of the Solute Carrier Family 10 Members NTCP, ASBT and SOAT.
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SOAT specifically transports sulfated steroid hormones and not bile acids, despite being the closest paralog of ASBT.
"In addition, sodium-dependent organic anion transporter SOAT specifically transports sulfated steroid hormones, but not bile acids."
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Taurolithocholic acid is nevertheless a sodium-dependent SOAT substrate and is the only substrate shared by NTCP, ASBT and SOAT.
"Surprisingly, SOAT showed significant sodium-dependent uptake of TLC and, therefore, TLC is the only common substrate of all three carriers NTCP, ASBT and SOAT, identified so far."
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Additional 7'- and/or 12'-hydroxylation blocks SOAT transport, which is why TCA, TCDCA and TDCA are not substrates.
"This is, however, not possible when TLC is additionally hydroxylated at the 7′ and/or 12’ positions, as it is the case for the BAs TCA, TCDCA, or TDCA, which all are not transported by SOAT."
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Whether taurolithocholate transport was present in the common NTCP/ASBT/SOAT ancestor or arose independently in the three carriers cannot currently be decided.
"However, the question if TLC was also a substrate of the common NTCP/ASBT/SOAT ancestor or if all three carriers later acquired the TLC transport function cannot be finally answered."
Role of the Sodium-Dependent Organic Anion Transporter (SOAT/SLC10A6) in Physiology and Pathophysiology.
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SOAT specifically transports 3'- and 17'-monosulfated steroid hormones into target cells, where they serve as precursors for intracrine formation of active estrogens and androgens.
"The sodium-dependent organic anion transporter (SOAT, gene symbol SLC10A6) specifically transports 3'- and 17'-monosulfated steroid hormones, such as estrone sulfate and dehydroepiandrosterone sulfate, into specific target cells."
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Sorting studies in transfected HEK293 cells localize SOAT to the plasma membrane.
"Sorting studies in transfected HEK293 cells clearly localized the SOAT protein to the plasma membrane"
Sodium-dependent organic anion transporter (Slc10a6(-/-)) knockout mice show normal spermatogenesis and reproduction, but elevated serum levels for cholesterol sulfate.
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SOAT/Soat is a plasma membrane transporter for sulfated steroids, highly expressed in testicular germ cells.
"SOAT (gene name SLC10A6 in man and Slc10a6 in mice) is a plasma membrane transporter for sulfated steroids, which is highly expressed in germ cells of the testis."
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Slc10a6-/- mice are fertile with normal litter size, spermatogenesis and sperm vitality, so Soat is not required for reproduction or is compensated.
"However, the Slc10a6-/- knockout mice were fertile, produced normal litter sizes, and had normal spermatogenesis and sperm vitality."
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Male Slc10a6-/- mice have elevated serum cholesterol sulfate.
"Interestingly, male Slc10a6-/- knockout mice showed significantly higher serum levels for cholesterol sulfate compared to their wildtype controls."
Homo- and heterodimerization is a common feature of the solute carrier family SLC10 members.
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SOAT is referred to as the steroid sulfate transporter of the SLC10 family.
"the steroid sulfate transporter SOAT"
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Heterodimerization occurs between most SLC10 carrier combinations, including SOAT.
"Heterodimerization was observed for most of the SLC10 carrier combinations."
Homo- and hetero-dimeric architecture of the human liver Na⁺-dependent taurocholate co-transporting protein.
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SLC10A6 co-immunoprecipitates and co-localizes with NTCP, showing that heteromeric SLC10 complexes form in vitro.
"SLC10A4 and SLC10A6 co-immunoprecipitated with NTCP, demonstrating that heteromeric complexes can be formed between SLC10A family members in vitro."
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Unlike SLC10A4, co-expression of SLC10A6 does not impair NTCP transport function.
"whereas expression of SLC10A6 or NTCP E257N, an inactive mutant, did not affect NTCP function."
Estrone-3-Sulfate Stimulates the Proliferation of T47D Breast Cancer Cells Stably Transfected With the Sodium-Dependent Organic Anion Transporter SOAT (SLC10A6).
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SOAT expression renders T47D breast cancer cells proliferative in response to physiological estrone-3-sulfate concentrations, and the effect is blocked by SOAT inhibition.
"Hormone-dependent breast cancer T47D cells, stably transfected with SOAT, showed significant proliferation after incubation with E1S at physiologically relevant concentrations."
A reference map of the human binary protein interactome.
SOAT can transport taurolithocholate-3-sulphate
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Reactome's own summary of this reaction states that SOAT, unlike other SLC10A proteins, has no affinity for bile acids and transports sulfo-conjugated bile acids such as taurolithocholate 3-sulphate.
"Unlike the other SLC10A gene products, SOAT shows no affinity for binding bile acids. However, SOAT is able to transport sulpho-conjugated bile acids such as taurolithocholate 3-sulphate (Geyer J et al, 2007)."
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Reactome notes that SOAT also transports structurally similar sulfated steroids and may deliver these prohormones to testis, pancreas and placenta.
"It can also transport the structurally similar sulphated steroids (not shown here), thus SOAT may play a role in delivery of these prohormones to testis, pancreas and placenta."
SLC-mediated bile acid transport
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R-HSA-9958517 is a container pathway that collects reactions categorized as SLC-mediated bile acid transport; SOAT enters it through the taurolithocholate-3-sulphate reaction.
"This pathway serves as collection of reactions categorized as SLC-mediated bile acid transport"
Annotation inferences using phylogenetic trees
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Combined Automated Annotation using Multiple IEA Methods