Development - S1P1 receptor signaling via beta-arrestin


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S1P1 receptor signaling via beta-arrestin

Sphingosine-1-phosphate receptor 1, also known as S1P1 receptor is a high affinity receptor for the bioactive lipid (2S,3R,4E)-Sphingosine 1-phosphate [1], [2]. Although the S1P1 receptor expression is very abundant in endothelial cells, transcripts related to S1P1 receptor are also detected at lower levels in vascular smooth muscle cells, fibroblasts, melanocytes, cells of epithelioid origin, brain [3], alveolar macrophages [4], cardiovascular tissues [5], natural killer cells and T cells [6].

S1P1 receptoris a G-protein coupled receptor which interacts with Guanine nucleotide binding protein alpha inhibiting G-protein alpha-i1, G-protein alpha-i2 and G-protein alpha-i3 and Guanine nucleotide binding protein, alpha activating G-protein alpha-o [7], [8].

Endocytosis of G-protein-coupled receptor signal complexes is required for activation of ERK1/2. Beta-arrestin1 is recruited to ligand-bound S1P1 receptor phosphorylated by GRK2. Beta-arrestin1 binds to Clathrin and activates Clathrin-mediated endocytosis [9].

c-Src is recruited to the PDGF-R-beta/ S1P1 receptor receptor complex. The recruited c-Src catalyses tyrosine phosphorylation of GAB1 and promotes accumulation of Dynamin-2 via GRB2. GAB1/ GRB2 complex activates. Active c-Src also promotes formation of GAB1/ GRB2/ PI3K cat class IA (p110-alpha) complex leading to activation of PI3K pathway and endocytosis of S1P1 receptor receptor [10], [11], [12], [13].

GRB2 activates H-Ras probably by SOS.

PtdIns(3,4,5)P3 possibly mediates SOS and GAB1 translocation to the plasma membrane.

H-Ras activates c-Raf-1 and triggers ERK1/2 activation through MEK1(MAP2K1) and MEK2(MAP2K2) [1], [7], [14], [15]. This leads to activation of ERK1/2 downstream targets including p90Rsk, p70 S6 kinase2 [16]. Activation of p70 S6 kinase2 presumably occurs via Tuberin/ mTOR pathway [17].

Activation of ERK1/2 was shown to mediate (2S,3R,4E)-Sphingosine 1-phosphate-induced endothelial cell survival (see anti-apoptosis [18].

Objects list:

(2S,3R,4E)-Sphingosine 1-phosphate Chemical IUPAC name (2S,3R,4E)-3-hydroxy-1-(phosphonooxy)octadec-4-en-2-aminium
Beta-arrestin1 Beta-arrestin-1
Clathrin Clathrin Group of complexes
Dynamin-2 Dynamin-2
ERK1/2 Erk 1/2 Protein group
G-protein alpha-i1 Guanine nucleotide-binding protein G(i) subunit alpha-1
G-protein alpha-i2 Guanine nucleotide-binding protein G(i) subunit alpha-2
G-protein alpha-i3 Guanine nucleotide-binding protein G(k) subunit alpha
G-protein alpha-o Guanine nucleotide-binding protein G(o) subunit alpha
GAB1 GRB2-associated-binding protein 1
GRB2 Growth factor receptor-bound protein 2
GRK2 Beta-adrenergic receptor kinase 1
H-Ras GTPase HRas
MEK1(MAP2K1) Dual specificity mitogen-activated protein kinase kinase 1
MEK2(MAP2K2) Dual specificity mitogen-activated protein kinase kinase 2
PDGF-R-beta Beta-type platelet-derived growth factor receptor
PI3K cat class IA (p110-alpha) Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
PtdIns(3,4,5)P3 PtdIns(3,4,5)P3 Compound group
S1P1 receptor Sphingosine 1-phosphate receptor 1
SOS SOS Protein group
Tuberin Tuberin
c-Raf-1 RAF proto-oncogene serine/threonine-protein kinase
c-Src Proto-oncogene tyrosine-protein kinase Src
mTOR Serine/threonine-protein kinase mTOR
p70 S6 kinase2 Ribosomal protein S6 kinase beta-2
p90Rsk p90 ribosomal S6 kinases Protein group


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    Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science (New York, N.Y.) 1998 Mar 6;279(5356):1552-5
  2. Van Brocklyn JR, Lee MJ, Menzeleev R, Olivera A, Edsall L, Cuvillier O, Thomas DM, Coopman PJ, Thangada S, Liu CH, Hla T, Spiegel S
    Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled receptor Edg-1 and intracellular to regulate proliferation and survival. The Journal of cell biology 1998 Jul 13;142(1):229-40
  3. Hla T, Maciag T
    An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. The Journal of biological chemistry 1990 Jun 5;265(16):9308-13
  4. Hornuss C, Hammermann R, Fuhrmann M, Juergens UR, Racké K
    Human and rat alveolar macrophages express multiple EDG receptors. European journal of pharmacology 2001 Oct 19;429(1-3):303-8
  5. Mazurais D, Robert P, Gout B, Berrebi-Bertrand I, Laville MP, Calmels T
    Cell type-specific localization of human cardiac S1P receptors. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 2002 May;50(5):661-70
  6. Jin Y, Knudsen E, Wang L, Bryceson Y, Damaj B, Gessani S, Maghazachi AA
    Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation. Blood 2003 Jun 15;101(12):4909-15
  7. Lee MJ, Evans M, Hla T
    The inducible G protein-coupled receptor edg-1 signals via the G(i)/mitogen-activated protein kinase pathway. The Journal of biological chemistry 1996 May 10;271(19):11272-9
  8. Windh RT, Lee MJ, Hla T, An S, Barr AJ, Manning DR
    Differential coupling of the sphingosine 1-phosphate receptors Edg-1, Edg-3, and H218/Edg-5 to the G(i), G(q), and G(12) families of heterotrimeric G proteins. The Journal of biological chemistry 1999 Sep 24;274(39):27351-8
  9. Alderton F, Rakhit S, Kong KC, Palmer T, Sambi B, Pyne S, Pyne NJ
    Tethering of the platelet-derived growth factor beta receptor to G-protein-coupled receptors. A novel platform for integrative signaling by these receptor classes in mammalian cells. The Journal of biological chemistry 2001 Jul 27;276(30):28578-85
  10. Rakhit S, Conway AM, Tate R, Bower T, Pyne NJ, Pyne S
    Sphingosine 1-phosphate stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle. Role of endothelial differentiation gene 1, c-Src tyrosine kinase and phosphoinositide 3-kinase. The Biochemical journal 1999 Mar 15;338 ( Pt 3):643-9
  11. Rakhit S, Pyne S, Pyne NJ
    The platelet-derived growth factor receptor stimulation of p42/p44 mitogen-activated protein kinase in airway smooth muscle involves a G-protein-mediated tyrosine phosphorylation of Gab1. Molecular pharmacology 2000 Aug;58(2):413-20
  12. Waters CM, Connell MC, Pyne S, Pyne NJ
    c-Src is involved in regulating signal transmission from PDGFbeta receptor-GPCR(s) complexes in mammalian cells. Cellular signalling 2005 Feb;17(2):263-77
  13. Singleton PA, Dudek SM, Chiang ET, Garcia JG
    Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and alpha-actinin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2005 Oct;19(12):1646-56
  14. Okamoto H, Takuwa N, Gonda K, Okazaki H, Chang K, Yatomi Y, Shigematsu H, Takuwa Y
    EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. The Journal of biological chemistry 1998 Oct 16;273(42):27104-10
  15. Miura S, Tanigawa H, Matsuo Y, Fujino M, Kawamura A, Saku K
    Ras/Raf1-dependent signal in sphingosine-1-phosphate-induced tube formation in human coronary artery endothelial cells. Biochemical and biophysical research communications 2003 Jul 11;306(4):924-9
  16. Lee MJ, Thangada S, Paik JH, Sapkota GP, Ancellin N, Chae SS, Wu M, Morales-Ruiz M, Sessa WC, Alessi DR, Hla T
    Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis. Molecular cell 2001 Sep;8(3):693-704
  17. Kluk MJ, Hla T
    Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration. Circulation research 2001 Sep 14;89(6):496-502
  18. Lee MJ, Thangada S, Claffey KP, Ancellin N, Liu CH, Kluk M, Volpi M, Sha'afi RI, Hla T
    Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 1999 Oct 29;99(3):301-12

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