Development - S1P1 signaling pathway

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S1P1 receptor signaling pathway

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 receptor is a G-protein coupled receptor which interacts with G-protein alpha-i1, G-protein alpha-i2 and G-protein alpha-i3 and G-protein alpha-o [7], [8].

G-protein alpha-i family members inhibit Adenylate cyclase activity. Thereby, binding of (2S,3R,4E)-Sphingosine 1-phosphate to S1P1 receptor significantly decreases Cyclic AMP level [2], [9].

(2S,3R,4E)-Sphingosine 1-phosphate binding to S1P1 receptor activates Phosphoinositide-3-kinase (PI3K)/ AKT1 cascade through G-protein alpha-i family-dependent mechanism [10]. PI3K / AKT1 pathway activation possibly occurs through G-protein beta/gamma subunits-mediated activation of c-Src which promotes formation of GAB1/ GRB2/ PI3K cat class IA (p110-alpha) complex leading to activation of PI3K pathway [11], [12], [13].

AKT1 phosphorylates the third intracellular loop of S1P1 receptor in activation-dependent manner. This event is essential for Rac1 activation [10]. Activation of PI3K/ AKT1 pathway leads to an interaction between Tiam1 with the phosphorylated S1P1 receptor. This interaction triggers Tiam1-mediated Rac1 GDP-GTP exchange [13].

Furthermore, AKT1 directly phosphorylates and activates eNOS leading to nitric oxide production [14]. AKT1 directly phosphorylates and inhibits GSK3 beta [10]. GSK3 beta inhibition results in increased cell viability [15].

VAV-1 is an important link between PI3K pathway and Rho GTPases which are necessary to promote (2S,3R,4E)-Sphingosine 1-phosphate-induced cell migration. VAV-1 activity is regulated by PI3K activation and PtdIns(3,4,5)P3 concentration. CDC42, RhoA and Rac1 are downstream targets of VAV-1 [16].

CDC42 and Rac1 regulate synthesis of Sphigosine-1-phosphate-induced cortical actin, whereas RhoA controls Sphigosine-1-phosphate-mediated stress fiber assembly, therefore promoting cell adhesion and cell motility [1], [17].

S1P1 receptor mobilizes Ca('2+) from intracellular pools through the G-protein beta/gamma mediated activation of PLC-beta and IP3 [9]. Ca('2+) release, possibly, promotes lymphangiogenesis [18].

CD69 forms a complex with S1P1 receptor, inhibiting function of S1P1 receptor receptor in lymphocyte egress [19].

CD44 association with S1P1 receptor induces transactivation of the latter receptor via its AKT1-dependent threonine phosphorylation. Consequent S1P1 receptor-induced Rac1 signaling leads to cortical actin thickening and barrier enhancement [20].



Objects list:

(2S,3R,4E)-Sphingosine 1-phosphate Chemical IUPAC name (2S,3R,4E)-3-hydroxy-1-(phosphonooxy)octadec-4-en-2-aminium
AKT1 RAC-alpha serine/threonine-protein kinase
Adenylate cyclase Adenylate cyclase Protein group
CD44 CD44 antigen
CD69 Early activation antigen CD69
CDC42 Cell division control protein 42 homolog
Ca('2+) Chemical IUPAC name calcium(+2) cation
Ca('2+) Chemical IUPAC name calcium(+2) cation
Cyclic AMP Chemical IUPAC name (1S,6R,8R,9R)-8-(6-amino-8-bromopurin-9-yl)-3-hydroxy-3-oxo-2,4,7-trioxa-35-phosphabicyclo[4.3.0]nonan-9-ol
G-protein alpha-i family G-protein alpha-i family 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
G-protein beta/gamma G-protein beta/gamma Group of complexes
GAB1 GRB2-associated-binding protein 1
GRB2 Growth factor receptor-bound protein 2
GSK3 beta Glycogen synthase kinase-3 beta
IP3 Chemical IUPAC name [(1R,2S,3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-diphosphonooxycyclohexyl] dihydrogen phosphate
PI3K cat class IA (p110-alpha) Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
PLC-beta Phospholipase C, beta Protein group
PtdIns(3,4,5)P3 PtdIns(3,4,5)P3 Compound group
Rac1 Ras-related C3 botulinum toxin substrate 1
RhoA Transforming protein RhoA
S1P1 receptor Sphingosine 1-phosphate receptor 1
Tiam1 T-lymphoma invasion and metastasis-inducing protein 1
VAV-1 Proto-oncogene vav
c-Src Proto-oncogene tyrosine-protein kinase Src
eNOS Nitric oxide synthase, endothelial

References:

  1. Lee MJ, Van Brocklyn JR, Thangada S, Liu CH, Hand AR, Menzeleev R, Spiegel S, Hla T
    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. 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
  10. 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
  11. 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
  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. De Palma C, Meacci E, Perrotta C, Bruni P, Clementi E
    Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: a novel pathway relevant to the pathophysiology of endothelium. Arteriosclerosis, thrombosis, and vascular biology 2006 Jan;26(1):99-105
  15. Zhang J, Honbo N, Goetzl EJ, Chatterjee K, Karliner JS, Gray MO
    Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia. American journal of physiology. Heart and circulatory physiology 2007 Nov;293(5):H3150-8
  16. Whetton AD, Lu Y, Pierce A, Carney L, Spooncer E
    Lysophospholipids synergistically promote primitive hematopoietic cell chemotaxis via a mechanism involving Vav 1. Blood 2003 Oct 15;102(8):2798-802
  17. Lee JF, Ozaki H, Zhan X, Wang E, Hla T, Lee MJ
    Sphingosine-1-phosphate signaling regulates lamellipodia localization of cortactin complexes in endothelial cells. Histochemistry and cell biology 2006 Sep;126(3):297-304
  18. Yoon CM, Hong BS, Moon HG, Lim S, Suh PG, Kim YK, Chae CB, Gho YS
    Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways. Blood 2008 Aug 15;112(4):1129-38
  19. Shiow LR, Rosen DB, Brdicková N, Xu Y, An J, Lanier LL, Cyster JG, Matloubian M
    CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 2006 Mar 23;440(7083):540-4
  20. Singleton PA, Dudek SM, Ma SF, Garcia JG
    Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family. The Journal of biological chemistry 2006 Nov 10;281(45):34381-93

  1. Lee MJ, Van Brocklyn JR, Thangada S, Liu CH, Hand AR, Menzeleev R, Spiegel S, Hla T
    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. 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
  10. 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
  11. 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
  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. De Palma C, Meacci E, Perrotta C, Bruni P, Clementi E
    Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: a novel pathway relevant to the pathophysiology of endothelium. Arteriosclerosis, thrombosis, and vascular biology 2006 Jan;26(1):99-105
  15. Zhang J, Honbo N, Goetzl EJ, Chatterjee K, Karliner JS, Gray MO
    Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia. American journal of physiology. Heart and circulatory physiology 2007 Nov;293(5):H3150-8
  16. Whetton AD, Lu Y, Pierce A, Carney L, Spooncer E
    Lysophospholipids synergistically promote primitive hematopoietic cell chemotaxis via a mechanism involving Vav 1. Blood 2003 Oct 15;102(8):2798-802
  17. Lee JF, Ozaki H, Zhan X, Wang E, Hla T, Lee MJ
    Sphingosine-1-phosphate signaling regulates lamellipodia localization of cortactin complexes in endothelial cells. Histochemistry and cell biology 2006 Sep;126(3):297-304
  18. Yoon CM, Hong BS, Moon HG, Lim S, Suh PG, Kim YK, Chae CB, Gho YS
    Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways. Blood 2008 Aug 15;112(4):1129-38
  19. Shiow LR, Rosen DB, Brdicková N, Xu Y, An J, Lanier LL, Cyster JG, Matloubian M
    CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 2006 Mar 23;440(7083):540-4
  20. Singleton PA, Dudek SM, Ma SF, Garcia JG
    Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family. The Journal of biological chemistry 2006 Nov 10;281(45):34381-93

Target Details

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