Follicular Fluid High-Density Lipoprotein-Associated Sphingosine 1-Phosphate (S1P) Promotes Human Granulosa Lutein Cell Migration via S1P Receptor Type 3 and Small G-Protein RAC11

We have recently reported that S1P (sphingosine-1-phosphate) differentially regulates cellular Rac activity and cell migration in either a positive or a negative direction via distinct G-protein-coupled receptor subtypes, i.e. S1P1/Edg1 (endothelial differentiation gene) and S1P2/Edg5 respectively, when each of the S1P receptor subtypes is expressed in CHO (Chinese-hamster ovary) cells. In B16F10 mouse melanoma cells, in which S1P2, but not the other S1P receptor subtypes, is endogenously expressed, S1P inhibited cell migration with concomitant inhibition of Rac and stimulation of RhoA in dose-dependent manners. Overexpression of S1P2 in the melanoma cells resulted in potentiation of S1P inhibition of both Rac and cell migration. In contrast, overexpression of S1P1 led to stimulation of cell migration, particularly at the lower S1P concentrations. Treatment of B16F10 cells with S1P inhibited lung metastasis 3 weeks after injection into mouse tail veins. Intriguingly, overexpression of S1P2 greatly potentiated the inhibition of metastasis by S1P, whereas that of S1P1 resulted in aggravation of metastasis. Suppression of cellular Rac activity by adenovirus-transduced expression of N17Rac, but not N19RhoA, strongly inhibited cell migration in vitro and lung metastasis in vivo. These results provide the first evidence that G-protein-coupled receptors could participate in the regulation of metastasis, in which ligand-dependent, subtype-specific regulation of the cellular Rac activity is probably critically involved as a mechanism.

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Sphingosine-1-phosphate: A bioactive lipid that confers high-density lipoprotein with vasculoprotection mediated by nitric oxide and prostacyclin

Thrombosis and Haemostasis ◽

10.1160/th08-10-0675 ◽

2009 ◽

Vol 101 (04) ◽

pp. 665-673 ◽

Cited By ~ 39

Author(s):

Lina Badimon ◽

Cristina Rodríguez ◽

María González-Díez ◽

José Martínez-González

Keyword(s):

Nitric Oxide ◽

High Density Lipoprotein ◽

G Protein ◽

Expression Patterns ◽

Density Lipoprotein ◽

High Density ◽

Coupling Mechanism ◽

Vascular Effects ◽

Wide Range ◽

Sphingosine 1 Phosphate

SummarySphingosine-1-phosphate (S1P) is a bioactive lipid generated in the intracellular membranes from the metabolism of sphingomyelin. Once secreted/exported by cells of haematopoietic origin and vascular cells S1P interacts with plasma proteins and accumulates in high-density lipoprotein (HDL). Growing evidence indicates that HDL-associated S1P is responsible for the beneficial effects of these lipoproteins on vasorelaxation, cell survival, cell adhesiveness, angiogenesis and synthesis of two powerful endogenous anti-atherogenic and anti-thrombotic molecules such as nitric oxide (NO) and prostacyclin (PGI2). It is likely that vascular effects of HDL-S1P are regulated by the local expression of S1P receptors. Five G protein-coupled receptors (S1P1 to S1P5), with differential expression patterns and dissimilar coupling mechanism to G protein subunits, have been identified in the vasculature. This review is focused on the central role of S1P as a bioactive component that confers vasculoprotective properties to HDL by eliciting a wide range of biological responses on endothelial and smooth muscle cells largely dependent on the up-regulation of NO and prostacyclin.

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Follicular Fluid High Density Lipoprotein-associated Sphingosine 1-Phosphate Is a Novel Mediator of Ovarian Angiogenesis

Journal of Biological Chemistry ◽

10.1074/jbc.m508759200 ◽

2005 ◽

Vol 281 (9) ◽

pp. 5398-5405 ◽

Cited By ~ 52

Author(s):

Sören von Otte ◽

Jürgen R. J. Paletta ◽

Steffi Becker ◽

Simone König ◽

Manfred Fobker ◽

...

Keyword(s):

High Density Lipoprotein ◽

Follicular Fluid ◽

Density Lipoprotein ◽

High Density ◽

Sphingosine 1 Phosphate

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Associations between follicular fluid high density lipoprotein particle components and embryo quality among in vitro fertilization patients

Journal of Assisted Reproduction and Genetics ◽

10.1007/s10815-016-0826-x ◽

2016 ◽

Vol 34 (1) ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

K. Kim ◽

M. S. Bloom ◽

R. W. Browne ◽

E. M. Bell ◽

R. M. Yucel ◽

...

Keyword(s):

In Vitro Fertilization ◽

High Density Lipoprotein ◽

Follicular Fluid ◽

Embryo Quality ◽

Density Lipoprotein ◽

High Density ◽

High Density Lipoprotein Particle ◽

Vitro Fertilization ◽

Lipoprotein Particle

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A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0611448104 ◽

2007 ◽

Vol 104 (18) ◽

pp. 7682-7687 ◽

Cited By ~ 503

Author(s):

Matthew R. Whorton ◽

Michael P. Bokoch ◽

Søren G. F. Rasmussen ◽

Bo Huang ◽

Richard N. Zare ◽

...

Keyword(s):

High Density Lipoprotein ◽

G Protein ◽

G Proteins ◽

Single Molecule ◽

Density Lipoprotein ◽

High Density ◽

Phospholipid Bilayer ◽

X Ray Crystallography ◽

Signaling Complex ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) respond to a diverse array of ligands, mediating cellular responses to hormones and neurotransmitters, as well as the senses of smell and taste. The structures of the GPCR rhodopsin and several G proteins have been determined by x-ray crystallography, yet the organization of the signaling complex between GPCRs and G proteins is poorly understood. The observations that some GPCRs are obligate heterodimers, and that many GPCRs form both homo- and heterodimers, has led to speculation that GPCR dimers may be required for efficient activation of G proteins. However, technical limitations have precluded a definitive analysis of G protein coupling to monomeric GPCRs in a biochemically defined and membrane-bound system. Here we demonstrate that a prototypical GPCR, the β2-adrenergic receptor (β2AR), can be incorporated into a reconstituted high-density lipoprotein (rHDL) phospholipid bilayer particle together with the stimulatory heterotrimeric G protein, Gs. Single-molecule fluorescence imaging and FRET analysis demonstrate that a single β2AR is incorporated per rHDL particle. The monomeric β2AR efficiently activates Gs and displays GTP-sensitive allosteric ligand-binding properties. These data suggest that a monomeric receptor in a lipid bilayer is the minimal functional unit necessary for signaling, and that the cooperativity of agonist binding is due to G protein association with a receptor monomer and not receptor oligomerization.

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Identification of a Novel Apolipoprotein, ApoN, in Ovarian Follicular Fluid

Endocrinology ◽

10.1210/en.2004-0630 ◽

2004 ◽

Vol 145 (11) ◽

pp. 5231-5242 ◽

Cited By ~ 4

Author(s):

Moira K. O’Bryan ◽

Lynda M. Foulds ◽

James F. Cannon ◽

Wendy R. Winnall ◽

Julie A. Muir ◽

...

Keyword(s):

Amino Acid ◽

High Density Lipoprotein ◽

Follicular Fluid ◽

Low Density Lipoprotein ◽

Regulatory Protein ◽

Amino Acid Level ◽

Density Lipoprotein ◽

High Density ◽

Significant Homology ◽

Ovarian Follicular Fluid

Abstract A novel apolipoprotein, designated ApoN, has been identified in bovine ovarian follicular fluid using chromatographic purification methods, amino acid sequence analysis, molecular biology, and bioinformatics. The apolipoprotein is a hydrophobic 12-kDa protein processed from the C terminus of a 29-kDa precursor expressed in a number of tissues, including the ovary, testis, the anterior chamber of the eye, skeletal muscle, uterus, and liver. Bovine, porcine, and murine ApoN display significant homology at the amino acid level across the entire precursor sequence. Surprisingly, there appears to be no orthologous protein in the human, although an APON-like pseudogene is found on chromosome 12. The N-terminal fragment of the ApoN precursor shows significant homology with the N-terminal sequence of the precursor of the cholesterol transport regulatory protein ApoF, but the corresponding C-terminal sequences of ApoN and ApoF possess no homology. ApoN is present in the high-density lipoprotein fraction of bovine serum and both the high-density lipoprotein and low-density lipoprotein fractions of bovine follicular fluid and is found in several tissues that are associated with local immunological privilege. These data suggest that ApoN may play a role in steroidogenesis and/or immunoregulation in the gonads of nonhuman species, as well as similar roles in other tissues.

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