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Gene Review

MBTPS1  -  membrane-bound transcription factor...

Homo sapiens

Synonyms: Endopeptidase S1P, KIAA0091, Membrane-bound transcription factor site-1 protease, PCSK8, S1P, ...
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Disease relevance of MBTPS1


Psychiatry related information on MBTPS1


High impact information on MBTPS1


Chemical compound and disease context of MBTPS1

  • Interestingly, tissue sphingosine content was elevated in the adenomas of Apc(Min/)(+) Sphk1(-/)(-) mice, whereas S1P levels were not significantly altered [10].
  • The stimulation of 70-kD fragment binding by nanomolar S1P, like stimulation of binding by LPA or nocodazole, was blocked by inactivation of Rho with C3 exotoxin but not by pertussis toxin-mediated inactivation of Gi [11].
  • Treatment with pertussis toxin, which ADP-ribosylates and inactivates G(i), blocked S1P-mediated inhibition of cAMP accumulation, but had no effect on c-Jun NH2-terminal kinase activation or inhibition of ERK1/2 [12].
  • The antiproliferative effect, like S1P-mediated ERK1/2 inhibition, was orthovanadate-sensitive and pertussis toxin-insensitive [12].
  • S1P-mediated NO production was suppressed by the addition of pertussis toxin, an inhibitor of G(i) proteins, the specific inhibitor of phospholipase C (PLC), and the Ca(2+) chelator BAPTA-AM [13].

Biological context of MBTPS1

  • Among the major substrates of SKI-1 are the sterol regulatory element-binding proteins, regulating cholesterol and fatty acid homeostasis [14].
  • Mutagenesis of the latter peptide allowed us to develop an efficiently processed SKI-1 substrate and to assess the importance of several P and P' residues [15].
  • Transient transfections data showed that, out of numerous mutants studied, the R134E prosegment mutant or the alpha(1)-AT reactive site loop variants RRVL(358), RRYL(358) and RRIL(358) are the best specific cellular inhibitors of SKI-1 [16].
  • Therefore, expression of the S1P gene may be under the control of SREBP-1, a key regulator of the expression of genes essential for intracellular lipid metabolism [17].
  • Exons 15-23 encode the hydrophilic carboxyl-terminal domains containing four copies of a motif called the Trp-Asp (WD) repeats that interact with and regulate SREBP and the site-1 protease [18].

Anatomical context of MBTPS1

  • Results revealed that Arg(130) and Arg(134) are critical for the autocatalytic primary processing of the prosegment and for the subsequent efficient exit of SKI-1 from the endoplasmic reticulum [14].
  • Biochemical and enzymatic characterization of the novel human subtilase hSKI-1 was carried out in various cell lines [15].
  • Site-1 protease (S1P) is a subtilisin-related enzyme that cleaves sterol regulatory element-binding proteins (SREBPs) in the lumen of endoplasmic reticulum, thereby initiating the release of transcriptionally active NH2-terminal fragments of SREBPs from membranes [17].
  • We observed that following S1P cleavage, the majority of the cleaved Luman was retained in cytoplasmic membranes, indicating that an additional step or enzymes yet to be identified are involved in complete cleavage and release to yield the product which ultimately enters the nuclei of cells [19].
  • Here we show that in mast cells, Sphk2 is required for production of S1P, for calcium influx, for activation of protein kinase C, and for cytokine production and degranulation [1].

Associations of MBTPS1 with chemical compounds

  • In addition, we have re-localized S1P and S2P to the ER with brefeldin A and find that the sequential cleavage of ATF6 is reconstituted in the ER [20].
  • This response is mediated by SREBP cleavage-activating protein (SCAP), a regulatory protein that activates S1P and also serves as a sterol sensor, losing its activity when sterols overaccumulate in cells [21].
  • The first is catalyzed by Site-1 protease (S1P), a membrane-bound subtilisin-related serine protease that cleaves the hydrophilic loop of SREBP that projects into the endoplasmic reticulum lumen [21].
  • Both ACTH and Bt2cAMP decreased cellular amounts of several sphingolipids, including sphingomyelin, ceramides, and sphingosine and stimulating the activity of sphingosine kinase and increasing the release of sphingosine-1-phosphate (S1P) into the media [22].
  • Analysis of the exon/intron structure revealed that the S1P gene consists of a mosaic of functional units: exon 1 encodes the 5' non-translated region; exon 2 encodes the NH2-terminal signal sequence; and exons 2 and 3 encode the pro-peptide sequence that is released when S1P is self-activated by intramolecular cleavage [17].

Physical interactions of MBTPS1

  • These studies suggest that sterols regulate the cleavage of SREBPs by modulating the ability of SCAP to transport SREBPs to a post-ER compartment that houses active Site-1 protease [23].

Enzymatic interactions of MBTPS1

  • CREB4 was cleaved in a site-specific manner in response to brefeldin A disruption of the Golgi or by coexpression with S1P but only after deletion or substitution of its C-terminal lumenal domain [24].

Regulatory relationships of MBTPS1


Other interactions of MBTPS1

  • We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis [27].
  • Processing of membrane-bound transcription factors such as sterol regulatory element-binding proteins (SREBPs) and the ER-stress response factor ATF6, and glycoproteins of some hemorrhagic fever viruses are initiated by the proprotein convertase SKI-1/S1P [16].
  • Our data demonstrate that SKI-1 is a Ca(2+)-dependent proteinase exhibiting optimal cleavage at pH 6 [15].
  • Thus, S1P cleavage of CREB4 may be suppressed by a determinant in the C-terminal region [24].
  • Furthermore, the effects of S-1-P on ICAM-1 expression were shown to be concentration dependent [26].

Analytical, diagnostic and therapeutic context of MBTPS1


  1. The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis. Olivera, A., Mizugishi, K., Tikhonova, A., Ciaccia, L., Odom, S., Proia, R.L., Rivera, J. Immunity (2007) [Pubmed]
  2. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Mitra, P., Oskeritzian, C.A., Payne, S.G., Beaven, M.A., Milstien, S., Spiegel, S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Oskouian, B., Sooriyakumaran, P., Borowsky, A.D., Crans, A., Dillard-Telm, L., Tam, Y.Y., Bandhuvula, P., Saba, J.D. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  4. Sphingosine 1-phosphate activates Weibel-Palade body exocytosis. Matsushita, K., Morrell, C.N., Lowenstein, C.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation. Jin, Y., Knudsen, E., Wang, L., Bryceson, Y., Damaj, B., Gessani, S., Maghazachi, A.A. Blood (2003) [Pubmed]
  6. Sphingosine-1-phosphate: characterization of its inhibition of platelet aggregation. Nugent, D., Xu, Y. Platelets (2000) [Pubmed]
  7. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Cyster, J.G. Annu. Rev. Immunol. (2005) [Pubmed]
  8. Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. DeBose-Boyd, R.A., Brown, M.S., Li, W.P., Nohturfft, A., Goldstein, J.L., Espenshade, P.J. Cell (1999) [Pubmed]
  9. Lysophospholipids as mediators of immunity. Lin, D.A., Boyce, J.A. Adv. Immunol. (2006) [Pubmed]
  10. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Kohno, M., Momoi, M., Oo, M.L., Paik, J.H., Lee, Y.M., Venkataraman, K., Ai, Y., Ristimaki, A.P., Fyrst, H., Sano, H., Rosenberg, D., Saba, J.D., Proia, R.L., Hla, T. Mol. Cell. Biol. (2006) [Pubmed]
  11. Sphingosine 1-phosphate stimulates fibronectin matrix assembly through a Rho-dependent signal pathway. Zhang, Q., Peyruchaud, O., French, K.J., Magnusson, M.K., Mosher, D.F. Blood (1999) [Pubmed]
  12. Nrg-1 belongs to the endothelial differentiation gene family of G protein-coupled sphingosine-1-phosphate receptors. Malek, R.L., Toman, R.E., Edsall, L.C., Wong, S., Chiu, J., Letterle, C.A., Van Brocklyn, J.R., Milstien, S., Spiegel, S., Lee, N.H. J. Biol. Chem. (2001) [Pubmed]
  13. Sphingosine 1-phosphate protects human umbilical vein endothelial cells from serum-deprived apoptosis by nitric oxide production. Kwon, Y.G., Min, J.K., Kim, K.M., Lee, D.J., Billiar, T.R., Kim, Y.M. J. Biol. Chem. (2001) [Pubmed]
  14. Biosynthesis and cellular trafficking of the convertase SKI-1/S1P: ectodomain shedding requires SKI-1 activity. Elagoz, A., Benjannet, S., Mammarbassi, A., Wickham, L., Seidah, N.G. J. Biol. Chem. (2002) [Pubmed]
  15. Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment. Touré, B.B., Munzer, J.S., Basak, A., Benjannet, S., Rochemont, J., Lazure, C., Chrétien, M., Seidah, N.G. J. Biol. Chem. (2000) [Pubmed]
  16. Development of protein-based inhibitors of the proprotein of convertase SKI-1/S1P: processing of SREBP-2, ATF6, and a viral glycoprotein. Pullikotil, P., Vincent, M., Nichol, S.T., Seidah, N.G. J. Biol. Chem. (2004) [Pubmed]
  17. Genomic structure and chromosomal mapping of the human site-1 protease (S1P) gene. Nakajima, T., Iwaki, K., Kodama, T., Inazawa, J., Emi, M. J. Hum. Genet. (2000) [Pubmed]
  18. Genomic structure and chromosomal mapping of the human sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) gene. Nakajima, T., Hamakubo, T., Kodama, T., Inazawa, J., Emi, M. J. Hum. Genet. (1999) [Pubmed]
  19. Luman, the cellular counterpart of herpes simplex virus VP16, is processed by regulated intramembrane proteolysis. Raggo, C., Rapin, N., Stirling, J., Gobeil, P., Smith-Windsor, E., O'Hare, P., Misra, V. Mol. Cell. Biol. (2002) [Pubmed]
  20. Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6. Shen, J., Prywes, R. J. Biol. Chem. (2004) [Pubmed]
  21. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Brown, M.S., Goldstein, J.L. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  22. Cyclic adenosine 5'-monophosphate-dependent sphingosine-1-phosphate biosynthesis induces human CYP17 gene transcription by activating cleavage of sterol regulatory element binding protein 1. Ozbay, T., Rowan, A., Leon, A., Patel, P., Sewer, M.B. Endocrinology (2006) [Pubmed]
  23. Sterols regulate cycling of SREBP cleavage-activating protein (SCAP) between endoplasmic reticulum and Golgi. Nohturfft, A., DeBose-Boyd, R.A., Scheek, S., Goldstein, J.L., Brown, M.S. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  24. CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P. Stirling, J., O'hare, P. Mol. Biol. Cell (2006) [Pubmed]
  25. A serine protease inhibitor prevents endoplasmic reticulum stress-induced cleavage but not transport of the membrane-bound transcription factor ATF6. Okada, T., Haze, K., Nadanaka, S., Yoshida, H., Seidah, N.G., Hirano, Y., Sato, R., Negishi, M., Mori, K. J. Biol. Chem. (2003) [Pubmed]
  26. Lysophospholipids increase ICAM-1 expression in HUVEC through a Gi- and NF-kappaB-dependent mechanism. Lee, H., Lin, C.I., Liao, J.J., Lee, Y.W., Yang, H.Y., Lee, C.Y., Hsu, H.Y., Wu, H.L. Am. J. Physiol., Cell Physiol. (2004) [Pubmed]
  27. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Ye, J., Rawson, R.B., Komuro, R., Chen, X., Davé, U.P., Prywes, R., Brown, M.S., Goldstein, J.L. Mol. Cell (2000) [Pubmed]
  28. Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. Ryu, J., Kim, H.J., Chang, E.J., Huang, H., Banno, Y., Kim, H.H. EMBO J. (2006) [Pubmed]
  29. Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action through a specific cell surface receptor. Postma, F.R., Jalink, K., Hengeveld, T., Moolenaar, W.H. EMBO J. (1996) [Pubmed]
  30. Sphingosine 1-phosphate protects rat liver sinusoidal endothelial cells from ethanol-induced apoptosis: Role of intracellular calcium and nitric oxide. Zheng, D.M., Kitamura, T., Ikejima, K., Enomoto, N., Yamashina, S., Suzuki, S., Takei, Y., Sato, N. Hepatology (2006) [Pubmed]
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