S1PR1

Last updated

S1PR1
3v2y.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases S1PR1 , CD363, CHEDG1, D1S3362, ECGF1, EDG-1, EDG1, S1P1, sphingosine-1-phosphate receptor 1
External IDs OMIM: 601974 MGI: 1096355 HomoloGene: 1071 GeneCards: S1PR1
Orthologs
SpeciesHumanMouse
Entrez

1901

13609

Ensembl

ENSG00000170989

ENSMUSG00000045092

UniProt

P21453

O08530

RefSeq (mRNA)

NM_001400
NM_001320730

NM_007901

RefSeq (protein)

NP_001307659
NP_001391

NP_031927

Location (UCSC) Chr 1: 101.24 – 101.24 Mb Chr 3: 115.5 – 115.51 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1PR1), also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded by the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5). [5] S1PR1 was originally identified as an abundant transcript in endothelial cells [6] and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation. [7] [8] In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking. [9] [10]

Contents

Structure

S1PR1 like the other members of the GPCR family is composed of seven-transmembrane helices arranged in a structurally conserved bundle. [5] As well as the other GPCRs, in the extracellular region S1PR1 is composed of three loops: ECL1 between helices II and III, ECL2 between helices IV and V and ECL3 between helices VI and VII. Compared to the other members of the family, S1PR1 has some specific features. The N-terminal of the protein folds as a helical cap above the top of the receptor and therefore it limits the access of the ligands to the amphipathic binding pocket. This marked amphipathicity is indeed in agreement with the zwitterionic nature of S1P. In addition, helices ECL1 and ECL2 pack tightly against the N-terminal helix, further occluding the access of the ligand from the extracellular space. S1P or S1P analogs are likely to reach the binding pocket from within the cell membrane and not from the extracellular space, may be through an opening between helices I and VII. Compared to the other GPCRs, this region is more open due to a different positioning of helices I and II toward helix III. [5] This occlusion of the ligand access space from the extracellular space could also explain the slow saturation of receptor binding in the presence of excess of ligand. [11]

Function

Like the other members of the GPCR family, S1PR1 senses its ligand from outside the cell and activates intracellular signal pathways that at last lead to cellular responses. The signal is transduced through the association of the receptor with different G proteins, which recruits a series of systems for downstream amplification of the signal. [12]

Immune system

S1PR1 activation is heavily involved in immune cell regulation and development. Sphingosine-1-phosphate receptor 1 is also involved in immune-modulation and directly involved in suppression of innate immune responses from T cells. [13] Depending on the G protein coupled with the S1PR1, diverse cellular effects are achieved: Gαi and Gαo modulate cellular survival, proliferation and motility; Gα12 and Gα13 modulate cytoskeletal remodeling and cell-shape changes and Gαq modulates several cellular effector functions. [12] All the intracellular functions occur via the interaction with Gαi and Gαo: these two proteins recruit other proteins for downstream amplification of the signal. [12] The main functions of S1P-S1PR1 system are as follows:

  1. The phosphatidylinositol 3-kinase (PI3K) and the lipid dependent protein kinase B (PKB) signaling pathway increases the survival of lymphocytes and other immune cells by inhibiting apoptosis.
  2. Phosphoinositide 3-kinase (PI3K) and the GTPase RAC are responsible of the lymphocytes migration and their interactions with other cells or with connective-tissue surfaces. [12] S1PR1-deficient thymocytes do not emigrate from the thymus, resulting in an increased numbers of mature thymocytes in the thymus and in medullary hyperplasia, and few S1PR1-deficient T cells can be detected in the blood, lymph nodes, spleen or non-lymphoid organs in these mouse models. [9] [10] The proliferation of immune cells is due to S1P-mediated signals via the GTPase RAS and extracellular-signal regulated kinase (ERK). IV) The Phospholipase C (PLC)-induced increases in intracellular calcium levels allow the secretion of cytokines and other immune mediators. [12]

Vasculogenesis

S1PR1 is one of the main receptors responsible for vascular growth and development, at least during embryogenesis. [14] In vascular endothelial cells the binding of S1P to S1PR1 induces migration, proliferation, cell survival and morphogenesis into capillary-like structures. [15] Moreover, the binding of S1P to S1PR1 is implicated in the formation of cell-cell adherens junctions, therefore inhibiting paracellular permeability of solutes and macromolecules. [16] [17] It was also shown in vivo that S1P synergizes with angiogenic factors such as FGF-2 and VEGF in inducing angiogenesis and vascular maturation through S1PR1. [17] [18] showed that S1PR1-KO mice died during development due to a defect in vascular stabilization, suggesting that this receptor is essential for vascular development. In conclusion, several evidences confirm that S1P via S1PR1 is a potent regulator of vascular growth and development, at least during embryogenesis. [14]

Clinical significance

Cancer

S1PR1 is involved in the motility of cancer cells upon stimulation by S1P. The signal pathway involves RAC-CDC42 and correlates with ERK1 and ERK2 activation. The RAC-CDC42 pathway leads to cell migration, whereas the ERK pathway leads to proliferation and neovascularization [19] [20] demonstrated that S1PR1 is strongly induced in endothelial cells during tumor angiogenesis and a siRNA against S1PR1 was able to inhibit angiogenesis and tumor growth. S1PR1 is also involved in other types of cancer: fibrosarcoma cells migrate upon activation of S1PR1 by S1P via RAC1–CDC42 dependent pathway) [21] [22] and ovarian cancer cell invasion involves S1PR1 or S1PR3 and calcium mobilization. [23]

Multiple sclerosis

S1PR1 is involved in multiple sclerosis. Fingolimod, a drug which internalizes the receptor, is approved as a disease modifying agent in MS. There are other Sphingosine-1-phosphate receptor modulators. Van Doorn et al. (2010) [24] observed a strong increase in S1PR1 (and S1PR3) expression in hypertrophic astrocytes both in the active and inactive MS lesions from MS patients compared to the unaffected patients.

Evolution

Paralogues for S1PR1 Gene [25]

Interactions

S1PR1 has been shown to interact with 5-HT1A receptor, [26] GNAI1, [27] and GNAI3. [27]

See also

Related Research Articles

<span class="mw-page-title-main">Pericyte</span> Cells associated with capillary linings

Pericytes are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood capillaries, where they communicate with endothelial cells by means of both direct physical contact and paracrine signaling. The morphology, distribution, density and molecular fingerprints of pericytes vary between organs and vascular beds. Pericytes help to maintain homeostatic and hemostatic functions in the brain, one of the organs with higher pericyte coverage, and also sustain the blood–brain barrier. These cells are also a key component of the neurovascular unit, which includes endothelial cells, astrocytes, and neurons. Pericytes have been postulated to regulate capillary blood flow and the clearance and phagocytosis of cellular debris in vitro. Pericytes stabilize and monitor the maturation of endothelial cells by means of direct communication between the cell membrane as well as through paracrine signaling. A deficiency of pericytes in the central nervous system can cause increased permeability of the blood–brain barrier.

<span class="mw-page-title-main">Sphingosine kinase</span> Class of enzymes

Sphingosine kinase (SphK) is a conserved lipid kinase that catalyzes formation sphingosine-1-phosphate (S1P) from the precursor sphingolipid sphingosine. Sphingolipid metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate, are lipid second messengers involved in diverse cellular processes. There are two forms of SphK, SphK1 and SphK2. SphK1 is found in the cytosol of eukaryotic cells, and migrates to the plasma membrane upon activation. SphK2 is localized to the nucleus.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.

The lysophospholipid receptor (LPL-R) group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eleven LPL receptors, each encoded by a separate gene. These LPL receptor genes are also sometimes referred to as "Edg".

<span class="mw-page-title-main">Death receptor 4</span> Protein found in humans

Death receptor 4 (DR4), also known as TRAIL receptor 1 (TRAILR1) and tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.

<span class="mw-page-title-main">CD69</span>

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

<span class="mw-page-title-main">LPAR1</span> Protein

Lysophosphatidic acid receptor 1 also known as LPA1 is a protein that in humans is encoded by the LPAR1 gene. LPA1 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">S1PR3</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 3 also known as S1PR3 is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P3.

<span class="mw-page-title-main">GPR6</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 6, also known as GPR6, is a protein which in humans is encoded by the GPR6 gene.

<span class="mw-page-title-main">S1PR4</span> Protein-coding gene in the species Homo sapiens

Sphingosine-1-phosphate receptor 4 also known as S1PR4 is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P4.

<span class="mw-page-title-main">LPAR2</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 2 also known as LPA2 is a protein that in humans is encoded by the LPAR2 gene. LPA2 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">S1PR2</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 2, also known as S1PR2 or S1P2, is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P).

<span class="mw-page-title-main">S1PR5</span> Protein-coding gene in the species Homo sapiens

Sphingosine-1-phosphate receptor 5 also known as S1PR5 is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P5.

<span class="mw-page-title-main">GPR3</span> Protein

G-protein coupled receptor 3 is a protein that in humans is encoded by the GPR3 gene. The protein encoded by this gene is a member of the G protein-coupled receptor family of transmembrane receptors and is involved in signal transduction.

<span class="mw-page-title-main">LPAR3</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 3 also known as LPA3 is a protein that in humans is encoded by the LPAR3 gene. LPA3 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">Vascular endothelial growth factor A</span> Protein involved in blood vessel growth

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

<span class="mw-page-title-main">SPHK2</span> Protein-coding gene in the species Homo sapiens

Sphingosine kinase 2 is a protein that in humans is encoded by the SPHK2 gene.

<span class="mw-page-title-main">Sphingosine-1-phosphate receptor</span>

The sphingosine-1-phosphate receptors are a class of G protein-coupled receptors that are targets of the lipid signalling molecule Sphingosine-1-phosphate (S1P). They are divided into five subtypes: S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5.

Find-me signals

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000045092 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  15. ↑ Lee MJ, Thangada S, Claffey KP, Ancellin N, Liu CH, Kluk M, Volpi M, Sha'afi RI, Hla T (October 1999). "Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate". Cell. 99 (3): 301–12. doi: 10.1016/S0092-8674(00)81661-X . PMID   10555146. S2CID   1126846.
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  18. ↑ Liu Y, Wada R, Yamashita T, Mi Y, Deng CX, Hobson JP, Rosenfeldt HM, Nava VE, Chae SS, Lee MJ, Liu CH, Hla T, Spiegel S, Proia RL (October 2000). "Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation". J. Clin. Invest. 106 (8): 951–61. doi:10.1172/JCI10905. PMC   314347 . PMID   11032855.
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  24. ↑ Van Doorn R, Van Horssen J, Verzijl D, Witte M, Ronken E, Van Het Hof B, Lakeman K, Dijkstra CD, Van Der Valk P, Reijerkerk A, Alewijnse AE, Peters SL, De Vries HE (September 2010). "Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions". Glia. 58 (12): 1465–76. doi:10.1002/glia.21021. PMID   20648639. S2CID   26000783.
  25. ↑ "GeneCards®: The Human Gene Database".
  26. ↑ Salim K, Fenton T, Bacha J, Urien-Rodriguez H, Bonnert T, Skynner HA, Watts E, Kerby J, Heald A, Beer M, McAllister G, Guest PC (May 2002). "Oligomerization of G-protein-coupled receptors shown by selective co-immunoprecipitation". J. Biol. Chem. 277 (18): 15482–5. doi: 10.1074/jbc.M201539200 . PMID   11854302.
  27. 1 2 Lee MJ, Evans M, Hla T (May 1996). "The inducible G protein-coupled receptor edg-1 signals via the G(i)/mitogen-activated protein kinase pathway". J. Biol. Chem. 271 (19): 11272–9. doi: 10.1074/jbc.271.19.11272 . PMID   8626678.

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