S1PR1

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S1PR1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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 MbChr 3: 115.5 – 115.51 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1PR1), also known as endothelial differentiation gene 1 (EDG1) is a

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]

Structure

S1PR1 like the other members of the

N terminus 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 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

Immune cell trafficking

S1P and its receptors play a key role in regulating immune cell trafficking by forming gradients that guide immune cells between tissues and vascular compartments. S1PR1 is pivotal in promoting T-cell egress from

lymphoid organs, while changes in S1P levels can influence immune cell migration and positioning in lymphoid and non-lymphoid tissues during inflammation or immune surveillance.[13]

S1PR1, primarily located on the cell membrane of most lymphocytes, binds to the abundant ligand S1P in the bloodstream to promote lymphocyte egress from lymphoid organs, allowing them to travel to affected tissues. S1PR1 is responsive to the S1P gradient between the lymphoid tissues (low S1P) and the

endothelial junctional contacts to close egress ports.[16]

Immune cell regulation

S1PR1 activation is heavily involved in

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 downstream effector 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

FGF-2 and VEGF in inducing angiogenesis and vascular maturation through S1PR1.[21] Liu et al. (2000) showed that S1PR1-KO mice died during development due to a defect in vascular stabilization, suggesting that this receptor is essential for vascular development.[22] In conclusion, several evidences confirm that S1P via S1PR1 is a potent regulator of vascular growth and development, at least during embryogenesis.[18]

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

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)[25][26] and ovarian cancer cell invasion involves S1PR1 or S1PR3 and calcium mobilization.[27]

Multiple sclerosis

S1PR1 is involved in multiple sclerosis. Fingolimod, a drug which internalizes the receptor, is approved as a disease modifying agent in Multiple sclerosis. There are other Sphingosine-1-phosphate receptor modulators. Van Doorn et al. (2010)

hypertrophic astrocytes
both in the active and inactive Multiple sclerosis lesions from patients compared to the unaffected patients.

Evolution

Paralogues for S1PR1 Gene[29]

Interactions

S1PR1 has been shown to interact with 5-HT1A receptor,[30] GNAI1,[31] and GNAI3.[31]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000170989 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000045092 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^
    PMID 22344443
    .
  6. PMID 2160972
    .
  7. PMID 9488656
    .
  8. PMID 10198065
    .
  9. ^
    PMID 14732704
    .
  10. ^
    S2CID 4371877
    .
  11. PMID 19231986
    .
  12. ^
    PMID 16099402
    .
  13. PMID 24597601
    .
  14. PMID 21159389
    .
  15. PMID 28475283
    .
  16. ^
    PMID 18787560
    .
  17. S2CID 21897008
    .
  18. ^
    PMID 15063179
    .
  19. S2CID 1126846
    .
  20. PMID 12954648
    .
  21. ^
    PMID 11544274
    .
  22. PMID 11032855
    .
  23. S2CID 32955497
    .
  24. PMID 15489955
    .
  25. PMID 17156449
    .
  26. PMID 17389600
    .
  27. PMID 17349972
    .
  28. S2CID 26000783
    .
  29. ^ "GeneCards®: The Human Gene Database".
  30. PMID 11854302
    .
  31. ^
    PMID 8626678
    .

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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