Lysophospholipid Receptors: Signaling and Biology

Ishii, Isao; Fukushima, Nobuyuki; Ye, Xiaoqin; Chun, Jerold

doi:10.1146/annurev.biochem.73.011303.073731

Cited by 713 publications

(678 citation statements)

References 208 publications

(286 reference statements)

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“…Expression of S1P receptors S1P 1 , S1P 2 and S1P 3 are broadly expressed in most of organs and mediate diverse actions of S1P (Table 1) [6][7][8]11]. Detailed expression patterns of S1P receptors in tissues were defined by analyzing mice in which -galactosidase (LacZ) reporter gene was knocked into the receptor gene loci.…”

Section: Blood S1p and S1p Transportersmentioning

confidence: 99%

“…In contrast to S1P 1 , S1P 2 and S1P 3 , the expression of the other two S1P receptors S1P 4 and S1P 5 is restricted: S1P 4 and S1P 5 are primarily expressed in lymphoid tissues and the lung, and the brain (especially oligodendrocytes), leukocytes and spleen, respectively [8,11].…”

Section: Blood S1p and S1p Transportersmentioning

confidence: 99%

“…S1P plays crucial roles in embryonic development and post-natal homeostasis in the cardiovascular, immune and nervous systems [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Sphingosine‐1‐phosphate signaling in physiology and diseases

et al. 2012

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Sphingosine-1-phosphate (S1P), which acts as both the extracellular and intracellular messenger, exerts pleiotropic biological activities including regulation of embryonic development, formation of the vasculature, vascular barrier integrity, vascular tonus and lymphocyte trafficking. Many of these S1P actions are mediated by five members of the G protein-coupled S1P receptors (S1P 1~S 1P 5 ) with overlapping but distinct coupling to heterotrimeric G proteins. S1P 1 couples exclusively to G i whereas S1P 2 and S1P 3 couple to multiple G proteins. S1P 2 and S1P 3 prefer G 12/13 and Gq, respectively, among others.The biological activities of S1P are based largely on the cellular actions of S1P on migration, adhesion and proliferation. Notably, S1P often exhibits bimodal effects in these cellular actions in a receptor subtype-specific manner. For example, S1P 1 mediates cell migration toward S1P, i.e. chemotaxis, via G i /Rac pathway whereas S1P 2 mediates inhibition of migration toward a chemoattractant, i.e. chemorepulsion, via G 12/13 /Rho pathway which induces Rac inhibition. In addition, S1P 1 mediates stimulation of cell proliferation through the G i -mediated signaling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and ERK whereas S1P 2 mediates inhibition of cell proliferation through mechanisms involving G 12/13 /Rho/Rho kinase/PTEN-dependent Akt inhibition.These differential effects of S1P receptor subtypes on migration and proliferation lead to antagonists with improved receptor subtype-selectivity and their optimal drug delivery system augments useful actions and attenuates deleterious effects of S1P, thus providing novel therapeutic tactics. Inhibitors or modulators of S1P-synthesizing and -metabolizing enzymes also could be potential therapeutic tools.

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Section: Blood S1p and S1p Transportersmentioning

confidence: 99%

Section: Blood S1p and S1p Transportersmentioning

confidence: 99%

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Sphingosine‐1‐phosphate signaling in physiology and diseases

et al. 2012

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“…Both LPA and S1P are found in high levels in malignant ovarian ascites, have similar enhancing effects on proliferation, and repression of apoptosis in vitro, and affect invasion [4][5][6][7][8][9]. LPA and S1P have potential beyond their mechanistic role in EOC progression as diagnostic and prognostic biomarkers [4,10,11].…”

Section: Introductionmentioning

confidence: 99%

“…S1P, like LPA, acts at the cell surface via G-protein coupled receptors (GPCRs). There are five known SP1 receptors encoded by members of the endothelial differentiation gene (Edg) family, S1P [1][2][3][4][5] [9]. We have recently shown that S1P regulates transcription and surface presentation of its own receptors [12].…”

Section: Introductionmentioning

confidence: 99%

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

Devine

Smicun

Hope

et al. 2008

Gynecologic Oncology

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OBJECTIVES-We previously demonstrated that sphingosine 1-phosphate (S1P) bimodally regulates epithelial ovarian cancer (EOC) cell invasiveness: low-concentration S1P stimulates invasion similar to lysophophatidic acid (LPA), while high-concentration S1P inhibits invasion. In this study, we investigated the mechanisms through which S1P affects EOC cell proteolysis, invasion, and adhesion in two cultured epithelial ovarian cancer cell lines. METHODS-G-proteinGi was inhibited by pertussis toxin (PTX) and GTP binding protein Rac by NSC23766. S1P conditioned media of DOV13 and OVCA429 cells were evaluated via gel zymography, fluorometric gelatinase assay, urokinase plasminogen activator (uPA) activity assay, and Western Blot for MT1-MMP. Cell invasion was analyzed in Matrigel chambers. Membrane-N-cadherin was localized via fluorescence microscopy.RESULTS-Zymography revealed pro-MMP2 in conditioned media of EOC cells regardless of treatment. Gelatinase activity was increased by low-concentration S1P. In DOV13 cells this effect was Gi and Rac dependent. In all OVCA429 and control DOV13 cells, PTX enhanced gelatinolysis, suggesting an MMP2-inhibitory pathway via Gi. MT1-MMP was decreased Gidependently by high-concentration S1P. Rac inhibition significantly counteracted low-S1P enhancement and high-S1P reduction of DOV13 invasiveness; and uPA activity in conditioned media of invading cells correlated significantly. Immunohistochemistry revealed Gi-dependent clustering of membrane-N-cadherin in DOV13 cells treated with 0.5µM S1P or 10µM LPA.CONCLUSIONS-S1P influences EOC invasion by regulating ECM-proteolysis and cell-cell attachment via MMP2, uPA, and membrane-N-cadherin. Furthermore, this study illustrates that the net effect of S1P on each of these processes reflects a complex interplay of multiple GPCR pathways involving Gi and downstream Rac.

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The molecular mechanism by which saturated lysophosphatidylcholine attenuates the metastatic capacity of melanoma cells

et al. 2016

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Lysophophatidylcholine (Lyso PC ) is an abundant constituent in human plasma. Patients with malignant cancer diseases have attenuated Lyso PC plasma levels, and thus Lyso PC has been examined as a metabolic biomarker for cancer prediction. Preclinical studies have shown that solid tumor cells drastically degrade Lyso PC s by incorporating their free fatty acids into cell membrane phospholipids. In this way, Lyso PC C18:0 reduced the metastatic spread of murine melanoma B16.F10 cells in mice. Although membrane rigidification may have a key role in the attenuation of metastasis, evidence for this has yet to be shown. Therefore, the present study aimed to determine how Lyso PC reduces the metastatic capacity of B16.F10 cells. Following cellular preincubation with Lyso PC C18:0 at increasing concentrations and lengths of time, cell migration was most significantly attenuated with 450 μ m Lyso PC C18:0 at 72 h. Biosensor measurements suggest that, despite their abundance in B16.F10 cells, Lyso PC ‐sensitive G protein‐coupled receptors do not appear to contribute to this effect. Instead, the attenuated migration appears to result from changes in cell membrane properties and their effect on underlying signaling pathways, most likely the formation of focal adhesion complexes. Treatment with 450 μ m Lyso PC C18:0 activates protein kinase C ( PKC )δ to phosphorylate syndecan‐4, accompanied by deactivation of PKC α. Subsequently, focal adhesion complex formation was attenuated, as confirmed by the reduced activity of focal adhesion kinase ( FAK ). Interestingly, 450 μ m Lyso PC C18:1 did not affect FAK activity, explaining its lower propensity to affect migration and metastasis. Therefore, membrane rigidification by Lyso PC C18:0 appears to prevent the formation of focal adhesion complexes, thus affecting integrin activity as a key for metastatic melanoma spread.

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Lysophospholipid Receptors: Signaling and Biology

Cited by 713 publications

References 208 publications

Sphingosine‐1‐phosphate signaling in physiology and diseases

Sphingosine‐1‐phosphate signaling in physiology and diseases

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

The molecular mechanism by which saturated lysophosphatidylcholine attenuates the metastatic capacity of melanoma cells

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