Sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, regulates various biological activities of vasculature. Most, if not all, S1P functions are mediated by the S1P family of G-protein-coupled receptors (GPCRs). Five S1P receptor subtypes (S1P1-S1P5) have been identified. Previously, we showed that S1P1, a Gi-coupled GPCR, regulates endothelial cytoskeletal architectures, chemotaxis, formation of adherens junctions (AJs) and tight junctions (TJs), as well as morphogenic and angiogenic responses. The S1P/ S1P1 signaling enhances the transendothelial electrical resistance (TEER), an indicator of vascular barrier integrity. Moreover, the S1P1-transduced signaling inhibits the histamine-induced vessel leakage in the Sprague Dawley (SD) rat. Mechanistically, S1P stimulation results in the formation of two distinct Zonula Occludens-1 (ZO-1) complexes which regulate the TJ formation and chemotactic response in endothelial cells (ECs). These results suggest that S1P signaling via the S1P1 receptor is important in the regulation of vascular functions. Importantly, we recently observed that S1P1 receptor is present in the nuclear compartment of ECs. Furthermore, we demonstrate that importin ?1 directly interacts with the third intracellular loop (i3) of S1P1 receptor and the nuclear translocation of S1P1 receptor is mediated by the importin ?1-Ran nuclear transport machinery. Inhibition of nuclear translocation of S1P1 has no effect on the initial S1P-mediated TEER rise, yet markedly diminishes its sustained rise. Furthermore, endothelial nuclear S1P-S1P1 signaling axis stimulates the transcription of Cyr61 and CTGF, two growth factors which are functionally important in angiogenesis. Together, these results suggest the central hypothesis of this proposal: "both the plasma membrane (PM-) and nuclear (N)-S1P1 receptors play critical roles in regulating endothelial functions, particularly in vascular integrity and angiogenesis". The main goal of this proposal is to characterize the respective signaling cascades and biological responses mediated by the PM- and N-S1P1 receptors with particular focus on the regulation of vessel integrity function and angiogenic response.
Three specific aims are planned in this proposal, and they are: (1) characterize the mechanisms of S1P1 receptor-mediated endothelial barrier integrity function, (2) determine the functions of nuclear S1P1 receptor in ECs, and (3) utilizing animal models to elucidate the physiological functions of S1P1 receptor in vivo. The success of this proposed research will not only lead to the discovery of novel mechanisms mediating GPCR signaling, but may also develop into future therapeutic usages.
Sphingosine-1-phosphate receptor subtype 1 (S1P1) is abundantly present in both plasma membrane and nuclear compartments of vascular endothelial cells. Recent evidence strongly suggests that plasma membrane S1P1 receptors play a critical role in the regulation of vascular barrier function; however, the function of nuclear S1P1 remains to be elucidated. The proposed research aims to characterize the molecular details and physiological relevance of plasma membrane and nuclear S1P1 receptor mediated signaling by using both in vitro and in vivo model systems.
|Honn, Kenneth V; Guo, Yande; Cai, Yinlong et al. (2016) 12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression. FASEB J 30:2360-9|
|Muradashvili, Nino; Khundmiri, Syed Jalal; Tyagi, Reeta et al. (2014) Sphingolipids affect fibrinogen-induced caveolar transcytosis and cerebrovascular permeability. Am J Physiol Cell Physiol 307:C169-79|
|Zhang, Wenliang; Mottillo, Emilio P; Zhao, Jiawei et al. (2014) Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity. J Biol Chem 289:32178-85|
|Zhang, Wenliang; An, Jin; Jawadi, Hiba et al. (2013) Sphingosine-1-phosphate receptor-2 mediated NFÎºB activation contributes to tumor necrosis factor-Î± induced VCAM-1 and ICAM-1 expression in endothelial cells. Prostaglandins Other Lipid Mediat 106:62-71|
|Zhang, Wenliang; Zhao, Jiawei; Lee, Jen-Fu et al. (2013) ETS-1-mediated transcriptional up-regulation of CD44 is required for sphingosine-1-phosphate receptor subtype 3-stimulated chemotaxis. J Biol Chem 288:32126-37|
|Liu, Jingjing; Zhao, Jiawei; Lee, Jen-Fu et al. (2013) 3-amino-4-(3-hexylphenylamino)-4-oxobutyl phosphonic acid (W146), a Selective Antagonist of Sphingosine-1-phospahte Receptor Subtype 1, Enhances AMD3100-stimulated Mobilization of Hematopoietic Stem Progenitor Cells in Animals. J Biochem Pharmacol Res 1:197-203|
|Hsu, Andrew; Zhang, Wenliang; Lee, Jen-Fu et al. (2012) 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. Int J Oncol 40:1619-26|
|Liu, Jingjing; Hsu, Andrew; Lee, Jen-Fu et al. (2011) To stay or to leave: Stem cells and progenitor cells navigating the S1P gradient. World J Biol Chem 2:1-13|
|Guo, Yande; Zhang, Wenliang; Giroux, Craig et al. (2011) Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid. J Biol Chem 286:33832-40|
|Dean, William L; Lee, Menq J; Cummins, Timothy D et al. (2009) Proteomic and functional characterisation of platelet microparticle size classes. Thromb Haemost 102:711-8|
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