Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors

Müllershausen, Florian; Zécri, Frédéric; Cetin, Cihan; Billich, Andreas; Guerini, Danilo; Seuwen, Klaus

doi:10.1038/nchembio.173

Cited by 319 publications

(279 citation statements)

References 44 publications

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“…Both S1P and aPC stimulation exerted similar effects, completely abrogating the TNF-dependent decrease in TEER, suggesting that the cytoprotective effects of aPC that we observed in ECs can be mediated by S1P signaling; however, the inhibition of S1P1 using FTY720 did not abolish the effect of aPC. FTY720 is an immunomodulator drug that has been proven to induce internalization of S1P1 in endothelial cells after 60 min of treatment (25). Here we pretreated the cells with FTY720 for 5 h before aPC stimulation, but found no difference in TEER values in the presence or absence of FTY720.…”

Section: Discussionmentioning

confidence: 93%

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Vetrano

Ploplis

Sala

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The protein C (PC) pathway is a well-characterized coagulation system. Endothelial PC receptors and thrombomodulin mediate the conversion of PC to its activated form, a potent anticoagulant and anti-inflammatory molecule. Here we show that the PC pathway is expressed on intestinal epithelial cells. The epithelial expression of PC and endothelial PC receptor is down-regulated In patients with inflammatory bowel disease. PC −/− /PC(Tg) mice, expressing only 3% of WT PC, developed spontaneous intestinal inflammation and were prone to severe experimental colitis. These mice also demonstrated spontaneous elevated production of inflammatory cytokines and increased intestinal permeability. Structural analysis of epithelial tight junction molecules revealed that lack of PC leads to decreased JAM-A and claudin-3 expression and an altered pattern of ZO-1 expression. In vitro, treatment of epithelial cells with activated PC led to protection of tight junction disruption induced by TNF-α, and in vivo, topical treatment with activated PC led to mucosal healing and amelioration of colitis. Taken together, these findings demonstrate that the PC pathway is a unique system involved in controlling intestinal homeostasis and inflammation by regulating epithelial barrier function.

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Section: Discussionmentioning

confidence: 93%

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Vetrano

Ploplis

Sala

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Binding of S1P receptor agonists, including FTY720 and CYM, to S1P receptors causes internalization and may cause functional antagonism, persistent signaling or both. 12,50,51 The ways in which internalization, degradation, and sustained signaling collectively regulate S1P receptor function are not yet understood. Further studies are needed to fully elucidate the molecular mechanism by which the S1P agonists act.…”

Section: Discussionmentioning

confidence: 99%

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

Cheng

Lin

et al. 2014

Cell Mol Immunol

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FTY720, an agonist for four of the five known sphingosine-1-phosphate (S1P) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple S1P receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective S1P receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an S1P 1 -selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an S1P 1 -selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.

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“…Sustained cAMP and G S signaling by receptor internalization in early endosomes was originally reported in 2009 for two distinct GPCRs, the thyroid-stimulating hormone receptor (TSHR) (35) and PTHR (2), and recently expanded to the dopamine D1 receptor (D1R) (36). Endosomal G-protein signaling appears to be an alternative pathway not only for G S -but also for inhibitory G protein (Gi)-coupled receptors, as demonstrated for the sphingosine-1-phosphate receptor (37). In keeping with the model that we present here, several questions remain to be studied, among them the following.…”

Section: Discussionmentioning

confidence: 99%

Noncanonical GPCR signaling arising from a PTH receptor–arrestin–Gβγ complex

Wehbi

Stevenson

Feinstein³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

140

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G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current "canonical" model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor-G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (G S )-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin-PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor-G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of G S activation and increases the steady-state levels of activated G S , leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.

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Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors

Cited by 319 publications

References 44 publications

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

Noncanonical GPCR signaling arising from a PTH receptor–arrestin–Gβγ complex

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