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PMID: 15764699 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

PTEN as an effector in the signaling of antimigratory G protein-coupled receptor.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 12 ·2005-03-22 ·Pages 4312-7

Sanchez T, Thangada S, Wu MT, Kontos CD, Wu D, Wu H, Hla T

Abstract

PTEN, a tumor suppressor phosphatase, is important in the regulation of cell migration and invasion. Physiological regulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) by cell surface receptors has not been described. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P), which acts through the S1P2 receptor (S1P2R) G protein-coupled receptor (GPCR) to inhibit cell migration, utilizes PTEN as a signaling intermediate. S1P2R inhibition of cell migration is abrogated by dominant-negative PTEN expression. S1P was unable to efficiently inhibit the migration of Pten(DeltaloxP/DeltaloxP) mouse embryonic fibroblasts; however, the antimigratory effect was restored upon the expression of PTEN. S1P2R activation of Rho GTPase is not affected in Pten(DeltaloxP/DeltaloxP) cells, and dominant-negative Rho GTPase reversed S1P inhibition of cell migration in WT cells but not in Pten(DeltaloxP/DeltaloxP) cells, suggesting that PTEN acts downstream of the Rho GTPase. Ligand activation of the S1P2R receptor stimulated the coimmunoprecipitation of S1P2R and PTEN. Interestingly, S1P2R signaling increased PTEN phosphatase activity in membrane fractions. Furthermore, tyrosine phosphorylation of PTEN was stimulated by S1P2R signaling. These data suggest that the S1P2R receptor actively regulates the PTEN phosphatase by a Rho GTPase-dependent pathway to inhibit cell migration. GPCR regulation of PTEN maybe a general mechanism in signaling events of cell migration and invasion.

MeSH Terms
Animals Cell Movement/physiology Cells, Cultured Humans Intracellular Signaling Peptides and Proteins Mice PTEN Phosphohydrolase Phosphoric Monoester Hydrolases/chemistry,metabolism Phosphorylation Protein Serine-Threonine Kinases/metabolism Protein Tyrosine Phosphatases/chemistry,deficiency,genetics,metabolism Receptors, Lysosphingolipid/genetics,metabolism Recombinant Proteins/genetics,metabolism Signal Transduction Transfection Tumor Suppressor Proteins/chemistry,deficiency,genetics,metabolism Tyrosine/chemistry rho GTP-Binding Proteins/metabolism rho-Associated Kinases
Chemicals
Intracellular Signaling Peptides and Proteins Receptors, Lysosphingolipid Recombinant Proteins Tumor Suppressor Proteins Tyrosine Protein Serine-Threonine Kinases rho-Associated Kinases Phosphoric Monoester Hydrolases Protein Tyrosine Phosphatases PTEN Phosphohydrolase PTEN protein, human Pten protein, mouse rho GTP-Binding Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Sanchez Teresa
Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Thangada Shobha
Wu Ming-Tao
Kontos Christopher D
Wu Dianqing
Wu Hong
Hla Timothy
References (51)
51 references, click to expand
  1. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association.
    Cell. 1999 Oct 29;99(3):323-34 PMID: 10555148
  2. Prostaglandin E(2) inhibits fibroblast migration by E-prostanoid 2 receptor-mediated increase in PTEN activity.
    Am J Respir Cell Mol Biol. 2005 Feb;32(2):135-41 PMID: 15539459
  3. Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2.
    Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4233-8 PMID: 10760291
  4. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation.
    J Clin Invest. 2000 Oct;106(8):951-61 PMID: 11032855
  5. Sphingosine 1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of alpha vbeta3- and beta1-containing integrins.
    J Biol Chem. 2001 Apr 13;276(15):11830-7 PMID: 11150298
  6. Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells.
    J Biol Chem. 2001 Aug 10;276(32):30359-65 PMID: 11387313
  7. Modulation of intracellular beta-catenin localization and intestinal tumorigenesis in vivo and in vitro by sphingolipids.
    Cancer Res. 2001 Sep 15;61(18):6723-9 PMID: 11559543
  8. Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis.
    Mol Cell. 2001 Sep;8(3):693-704 PMID: 11583630
  9. Lysophospholipids--receptor revelations.
    Science. 2001 Nov 30;294(5548):1875-8 PMID: 11729304
  10. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex.
    J Biol Chem. 2001 Dec 28;276(52):48627-30 PMID: 11707428
  11. Sphingosine-1-phosphate, a platelet-derived lysophospholipid mediator, negatively regulates cellular Rac activity and cell migration in vascular smooth muscle cells.
    Circ Res. 2002 Feb 22;90(3):325-32 PMID: 11861422
  12. PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects.
    J Biol Chem. 2002 Mar 29;277(13):10760-6 PMID: 11784722
  13. Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity.
    Oncogene. 2002 Apr 4;21(15):2357-64 PMID: 11948419
  14. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate.
    Cell. 1999 Oct 29;99(3):301-12 PMID: 10555146
  15. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
    Science. 2002 Apr 12;296(5566):346-9 PMID: 11923495
  16. The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
    J Biol Chem. 2002 Jun 14;277(24):21453-7 PMID: 11967257
  17. Tumor suppressor PTEN mediates sensing of chemoattractant gradients.
    Cell. 2002 May 31;109(5):599-610 PMID: 12062103
  18. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis.
    Cell. 2002 May 31;109(5):611-23 PMID: 12062104
  19. Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (S1P) receptors, S1P(2)/LP(B2)/EDG-5 and S1P(3)/LP(B3)/EDG-3.
    J Biol Chem. 2002 Jul 12;277(28):25152-9 PMID: 12006579
  20. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB.
    Cell. 2002 Oct 18;111(2):251-63 PMID: 12408869
  21. Inhibitory and stimulatory regulation of Rac and cell motility by the G12/13-Rho and Gi pathways integrated downstream of a single G protein-coupled sphingosine-1-phosphate receptor isoform.
    Mol Cell Biol. 2003 Mar;23(5):1534-45 PMID: 12588974
  22. Membrane-binding and activation mechanism of PTEN.
    Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7491-6 PMID: 12808147
  23. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils.
    Cell. 2003 Jul 25;114(2):201-14 PMID: 12887922
  24. Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades.
    J Biol Chem. 2003 Oct 10;278(41):40057-66 PMID: 12869565
  25. Regulation of cell migration by the C2 domain of the tumor suppressor PTEN.
    Science. 2004 Feb 20;303(5661):1179-81 PMID: 14976311
  26. Point-counterpoint of sphingosine 1-phosphate metabolism.
    Circ Res. 2004 Apr 2;94(6):724-34 PMID: 15059942
  27. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis.
    J Biol Chem. 2004 Jul 9;279(28):29367-73 PMID: 15138255
  28. Physiological and pathological actions of sphingosine 1-phosphate.
    Semin Cell Dev Biol. 2004 Oct;15(5):513-20 PMID: 15271296
  29. High-efficiency transformation of mammalian cells by plasmid DNA.
    Mol Cell Biol. 1987 Aug;7(8):2745-52 PMID: 3670292
  30. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors.
    J Biol Chem. 1990 Jun 5;265(16):9308-13 PMID: 2160972
  31. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors.
    Cell. 1992 Aug 7;70(3):389-99 PMID: 1643657
  32. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling.
    Cell. 1992 Aug 7;70(3):401-10 PMID: 1643658
  33. Sphingosine-1-phosphate inhibits PDGF-induced chemotaxis of human arterial smooth muscle cells: spatial and temporal modulation of PDGF chemotactic signal transduction.
    J Cell Biol. 1995 Jul;130(1):193-206 PMID: 7790372
  34. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95.
    Science. 1995 Sep 22;269(5231):1737-40 PMID: 7569905
  35. The inducible G protein-coupled receptor edg-1 signals via the G(i)/mitogen-activated protein kinase pathway.
    J Biol Chem. 1996 May 10;271(19):11272-9 PMID: 8626678
  36. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.
    Science. 1997 Mar 28;275(5308):1943-7 PMID: 9072974
  37. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.
    Nat Genet. 1997 Apr;15(4):356-62 PMID: 9090379
  38. Regulated membrane localization of Tiam1, mediated by the NH2-terminal pleckstrin homology domain, is required for Rac-dependent membrane ruffling and C-Jun NH2-terminal kinase activation.
    J Cell Biol. 1997 Apr 21;137(2):387-98 PMID: 9128250
  39. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.
    Nat Genet. 1997 May;16(1):64-7 PMID: 9140396
  40. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1.
    Science. 1998 Mar 6;279(5356):1552-5 PMID: 9488656
  41. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.
    J Biol Chem. 1998 May 29;273(22):13375-8 PMID: 9593664
  42. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.
    Science. 1998 Jun 5;280(5369):1614-7 PMID: 9616126
  43. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.
    Cell. 1998 Oct 2;95(1):29-39 PMID: 9778245
  44. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis.
    Genes Dev. 1999 Feb 1;13(3):295-306 PMID: 9990854
  45. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems.
    Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1563-8 PMID: 9990064
  46. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway.
    Proc Natl Acad Sci U S A. 1999 May 25;96(11):6199-204 PMID: 10339565
  47. Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5.
    J Biol Chem. 1999 Jul 2;274(27):18997-9002 PMID: 10383399
  48. The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region.
    Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10182-7 PMID: 10468583
  49. 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.
    J Biol Chem. 1999 Sep 24;274(39):27351-8 PMID: 10488065
  50. Ephrins and their Eph receptors: multitalented directors of embryonic development.
    EMBO J. 1999 Oct 1;18(19):5159-65 PMID: 10508149
  51. Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases.
    Curr Biol. 2000 Apr 6;10(7):401-4 PMID: 10753747
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0409784102
Published
2005-03-22
Epub
2005-00-11
Pages
4312-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC555509
Subset
IM
Grants
NHLBI NIH HHS · HL70694 · United States
NHLBI NIH HHS · P01 HL070694 · United States
NHLBI NIH HHS · R37 HL067330 · United States
NHLBI NIH HHS · R01 HL067330 · United States
NHLBI NIH HHS · HL67330 · United States
External Links
PubMed source DOI: 10.1073/pnas.0409784102 PMC Full Text View journal details
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