Ligand-induced nuclear translocation of S1P1 receptors mediates Cyr61 and CTGF transcription in endothelial cells

Abstract

Sphingosine-1-phosphate (S1P) receptor subtype 1 (S1P 1 ), a G-protein coupled receptor (GPCR), regulates many biological activities of endothelial cells (ECs). In this report, we show that S1P 1 receptors are present in the nuclei of ECs by using various biochemical and microscopic techniques such as cellular fractionation, immunogold labeling, and confocal microscopic analysis. Live cell imaging showed that plasma membrane S1P 1 receptors are rapidly internalized and subsequently translocated to nuclear compartment upon S1P stimulation. Utilizing membrane biotinylation technique further supports the notion that nuclear S1P 1 receptors were internalized from plasma membrane S1P 1 after ligand treatment. Moreover, nuclear S1P 1 is able to regulate the transcription of Cyr61 and CTGF, two growth factors functionally important in the regulation of vasculature. Collectively, these data suggest a novel S1P-S1P 1 signaling axis present in the nuclear compartment of endothelial cells, which may regulate biological responses of endothelium.

Sphingosine-1-phosphate receptor-3 signaling up-regulates epidermal growth factor receptor and enhances epidermal growth factor receptor-mediated carcinogenic activities in cultured lung adenocarcinoma cells

“…3A). Next, we performed nuclear run-off analysis (28) to examine whether the S1P-induced EGFR up-regulation is controlled at the transcriptional level. As shown in Fig.…”

Osteoblast regulation via ligand-activated nuclear trafficking of the oxytocin receptor

“…In fact, molecules that have traditionally been considered part of the plasma membrane and cytosol have also been widely described in the nucleus. Nuclear localization has been documented for the CCR2, VPAC1, S1P1, and CXCR4 receptors, which in certain cases, are mediated by Tnpo1 (17)(18)(19). In contrast, GnRHR, mGluR5, and βARs have been found in the nuclear membrane.…”

“…Although G proteins have been found in the Golgi body, endoplasmic reticulum, and cytoskeleton (11)(12)(13), GPCRs can localize to the nucleus or nuclear membrane (14)(15)(16). For example, on treatment with sphingosine-1-phosphate (S1P), the S1P receptor subtype 1 can translocate to endothelial cell nuclei to activate transcription (17). Likewise, chemokine receptor 2 (CCR2), expressed in monocyte, has been shown to interact directly with transportin-1 (Tnpo1) to undergo nuclear localization (18).…”

Extending the knowledge in histochemistry and cell biology

“…Wang et al (2008a) also studied endothelial cells, but shifted their focus on integrin-mediated signaling. The authors showed that sphingosine-1-phosphate (S1P), a bioactive lipid mediator for various endothelial processes including proliferation, adhesion and chemotaxis (Kim et al 2009c), activated integrin v 3 in lamellipodia of endothelial cells via the S1P receptor subtype 1, which in another study of the group had been shown to shuttle to the nucleus (Estrada et al 2009). S1P further induced association of focal adhesion kinase and cytoskeletal proteins with integrin v 3 and promoted enhanced endothelial migration on vitronectin-coated substrata.…”