Disease relevance of MBTPS1

• However, susceptibility to in vivo anaphylaxis is determined both by S1P within the mast cell compartment and by circulating S1P generated by Sphk1 predominantly from a non-mast cell source(s) [1].
• Mast cells play a pivotal role in inflammatory and immediate-type allergic reactions by secreting a variety of potent inflammatory mediators, including sphingosine-1-phosphate (S1P) [2].
• Down-regulation of S1P phosphatases was also observed, suggesting that colon cancer cells manifest a block in S1P catabolism [3].
• We now show that S1P activates endothelial cell exocytosis of Weibel-Palade bodies, releasing vasoactive substances capable of causing vascular thrombosis and inflammation [4].
• Pretreatment of T cells with pertussis toxin (PTX) blocked the inhibitory effect of S1P on activation with PMA plus ionomycin, but not on activation with anti-CD3 plus anti-CD28 [5].

Psychiatry related information on MBTPS1

• S1P also increased the response time of platelets to arachidonic acid (AA), but decreased the response time to PMA [6].

High impact information on MBTPS1

• Two families of G protein-coupled receptors play essential roles in lymphocyte migration through these organs: chemokine receptors and sphingosine-1-phosphate (S1P) receptors [7].
• S1P receptor-1 is required for lymphocyte egress from thymus and secondary lymphoid organs and is downregulated by the immunosuppressive drug FTY720 [7].
• Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi [8].
• In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi, where SREBPs are cleaved by Site-1 protease (S1P) [8].
• Lysophospholipids (LPLs) are lipid-derived signaling molecules exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) [9].

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

• AEBSF also inhibited production of the mature form of SREBP-2 that was induced in response to sterol depletion, and appeared to directly prevent cleavage of ATF6alpha and ATF6beta by inhibiting Site-1 protease [25].
• This study showed that LPA and S-1-P enhance ICAM-1 expression at both the mRNA and protein levels in human umbilical cord vein endothelial cells (HUVECs) [26].

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

• Site-directed mutagenesis, in vitro cleavage of a synthetic peptide containing the shedding site, and inhibitor studies favor an autocatalytic event occurring at a non-canonical SKI-1 recognition sequence, with P2 and P1 Leu being very critical [14].
• In the experiments reported here, we localized the human S1P gene to chromosome 16q24 by fluorescent in situ hybridization and radiation-hybrid mapping, and determined its genomic structure [17].
• We evaluated the role of SPHK1 and S1P in osteoclastogenesis using bone marrow-derived macrophage (BMM) single and BMM/osteoblast coculture systems [28].
• Microinjection of S1P has no effect, neither has addition of sphingosine or ceramide [29].
• Electron microscopy confirmed this protective effect of S1P on damaged SECs in liver tissues after perfusion of ethanol [30].

References