Skip to main content
SpringerLink
Log in

Phosphatidylserine-Mediated Cellular Signaling

  • Chapter
  • First Online:
Lipid-mediated Protein Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 991))

Abstract

Phosphatidylserine (PS), a phospholipid with a negatively charged head group, is an important constituent of eukaryotic membranes. Rather than being a passive component of cellular membranes, PS plays an important role in a number of signaling pathways. Signaling is mediated by proteins that are recruited and/or activated by PS in one of two ways: via domains that stereospecifically recognize the head group, or by electrostatic interactions with membranes that are rich in PS and therefore display negative surface charge. Such interactions are key to both intracellular and extracellular signaling cascades. PS, exposed extracellularly, is instrumental in triggering blood clotting and also serves as an “eat me” signal for the clearance of apoptotic cells. Inside the cell, a number of pathways depend of PS; these include kinases, small GTPases and fusogenic proteins. This review will discuss the generation and distribution of PS, current methods of phospholipid visualization within live cells, as well as the current understanding of the role of PS in both extracellular and intracellular signaling events.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ajiro K, Bortner CD, Westmoreland J, Cidlowski JA (2008) An endogenous calcium-dependent, caspase-independent intranuclear degradation pathway in thymocyte nuclei: antagonism by physiological concentrations of K(+) ions. Exp Cell Res 314:1237–1249

    PubMed  CAS  Google Scholar 

  2. Aleshin A, Finn RS (2010) SRC: a century of science brought to the clinic. Neoplasia 12:599–607

    PubMed  CAS  Google Scholar 

  3. Andersen MH, Graversen H, Fedosov SN et al (2000) Functional analyses of two cellular binding domains of bovine lactadherin. Biochemistry 39:6200–6206

    PubMed  CAS  Google Scholar 

  4. Anderson HA, Maylock CA, Williams JA et al (2003) Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol 4:87–91

    PubMed  CAS  Google Scholar 

  5. Andree HA, Reutelingsperger CP, Hauptmann R et al (1990) Binding of vascular anticoagulant alpha (VAC alpha) to planar phospholipid bilayers. J Biol Chem 265:4923–4928

    PubMed  CAS  Google Scholar 

  6. Angelillo-Scherrer A, Burnier L, Lambrechts D et al (2008) Role of Gas6 in erythropoiesis and anemia in mice. J Clin Invest 118:583–596

    PubMed  CAS  Google Scholar 

  7. Aoki J, Nagai Y, Hosono H et al (2002) Structure and function of phosphatidylserine-specific phospholipase A1. Biochim Biophys Acta 1582:26–32

    PubMed  CAS  Google Scholar 

  8. Arikketh D, Nelson R, Vance JE (2008) Defining the importance of phosphatidylserine synthase-1 (PSS1): unexpected viability of PSS1-deficient mice. J Biol Chem 283:12888–12897

    PubMed  CAS  Google Scholar 

  9. Atkinson K, Fogel S, Henry SA (1980) Yeast mutant defective in phosphatidylserine synthesis. J Biol Chem 255:6653–6661

    PubMed  CAS  Google Scholar 

  10. Augereau O, Rossignol R, DeGiorgi F et al (2004) Apoptotic-like mitochondrial events associated to phosphatidylserine exposure in blood platelets induced by local anaesthetics. Thromb Haemost 92:104–113

    PubMed  CAS  Google Scholar 

  11. Bai J, Wang P, Chapman ER (2002) C2A activates a cryptic Ca(2+)-triggered membrane penetration activity within the C2B domain of synaptotagmin I. Proc Natl Acad Sci U S A 99:1665–1670

    PubMed  CAS  Google Scholar 

  12. Bakowski MA, Braun V, Lam GY et al (2010) The phosphoinositide phosphatase SopB manipulates membrane surface charge and trafficking of the Salmonella-containing vacuole. Cell Host Microbe 7:453–462

    PubMed  CAS  Google Scholar 

  13. Balasubramanian K, Mirnikjoo B, Schroit AJ (2007) Regulated externalization of phosphatidylserine at the cell surface: implications for apoptosis. J Biol Chem 282:18357–18364

    PubMed  CAS  Google Scholar 

  14. Bayascas JR (2008) Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways. Cell Cycle 7:2978–2982

    PubMed  CAS  Google Scholar 

  15. Bellini F, Bruni A (1993) Role of a serum phospholipase A1 in the phosphatidylserine-induced T cell inhibition. FEBS Lett 316:1–4

    PubMed  CAS  Google Scholar 

  16. Bergo MO, Gavino BJ, Steenbergen R et al (2002) Defining the importance of phosphatidylserine synthase 2 in mice. J Biol Chem 277:47701–47708

    PubMed  CAS  Google Scholar 

  17. Bevers EM, Comfurius P, van Rijn JL et al (1982) Generation of prothrombin-converting activity and the exposure of phosphatidylserine at the outer surface of platelets. Eur J Biochem 122:429–436

    PubMed  CAS  Google Scholar 

  18. Bevers EM, Wiedmer T, Comfurius P et al (1992) Defective Ca(2+)-induced microvesiculation and deficient expression of procoagulant activity in erythrocytes from a patient with a bleeding disorder: a study of the red blood cells of Scott syndrome. Blood 79:380–388

    PubMed  CAS  Google Scholar 

  19. Bevers EM, Williamson PL (2010) Phospholipid scramblase: an update. FEBS Lett 584:2724–2730

    PubMed  CAS  Google Scholar 

  20. Béguin S, Kumar R (1997) Thrombin, fibrin and platelets: a resonance loop in which von Willebrand factor is a necessary link. Thromb Haemost 78:590–594

    PubMed  Google Scholar 

  21. Boehning D, Patterson RL, Sedaghat L et al (2003) Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat Cell Biol 5:1051–1061

    PubMed  CAS  Google Scholar 

  22. Bollen IC, Higgins JA (1980) Phospholipid asymmetry in rough- and smooth-endoplasmic-reticulum membranes of untreated and phenobarbital-treated rat liver. Biochem J 189:475–480

    PubMed  CAS  Google Scholar 

  23. Boon JM, Smith BD (2002) Chemical control of phospholipid distribution across bilayer membranes. Med Res Rev 22:251–281

    PubMed  CAS  Google Scholar 

  24. Borisenko GG, Matsura T, Liu S-X et al (2003) Macrophage recognition of externalized phosphatidylserine and phagocytosis of apoptotic Jurkat cells–existence of a threshold. Arch Biochem Biophys 413:41–52

    PubMed  CAS  Google Scholar 

  25. Bradshaw JM (2010) The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cell Signal 22:1175–1184

    PubMed  CAS  Google Scholar 

  26. Brose N, Petrenko AG, Sudhof TC, Jahn R (1992) Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science 256:1021–1025

    PubMed  CAS  Google Scholar 

  27. Calderon F, Kim H-Y (2008) Detection of intracellular phosphatidylserine in living cells. J Neurochem 104:1271–1279

    PubMed  CAS  Google Scholar 

  28. Castoldi E, Collins PW, Williamson PL, Bevers EM (2011) Compound heterozygosity for 2 novel TMEM16F mutations in a patient with Scott syndrome. Blood 117:4399–4400

    PubMed  CAS  Google Scholar 

  29. Chattopadhyay A, London E (1987) Parallax method for direct measurement of membrane penetration depth utilizing fluorescence quenching by spin-labeled phospholipids. Biochemistry 26:39–45

    PubMed  CAS  Google Scholar 

  30. Chattopadhyay A, London E (1988) Spectroscopic and ionization properties of N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-labeled lipids in model membranes. Biochim Biophys Acta 938:24–34

    PubMed  CAS  Google Scholar 

  31. Chen CY, Ingram MF, Rosal PH, Graham TR (1999) Role for Drs2p, a P-type ATPase and potential aminophospholipid translocase, in yeast late Golgi function. J Cell Biol 147:1223–1236

    PubMed  CAS  Google Scholar 

  32. Cosemans JMEM, Van Kruchten R, Olieslagers S et al (2010) Potentiating role of Gas6 and Tyro3, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization. J Thromb Haemost 8:1797–1808

    PubMed  CAS  Google Scholar 

  33. Dachary-Prigent J, Pasquet JM, Freyssinet JM, Nurden AT (1995) Calcium involvement in aminophospholipid exposure and microparticle formation during platelet activation: a study using Ca2  +  −ATPase inhibitors. Biochemistry 34:11625–11634

    PubMed  CAS  Google Scholar 

  34. Daleke DL (2006) Phospholipid flippases. J Biol Chem 282:821–825

    PubMed  Google Scholar 

  35. Daleke DL (2003) Regulation of transbilayer plasma membrane phospholipid asymmetry. J Lipid Res 44:233–242

    PubMed  CAS  Google Scholar 

  36. Darland-Ransom M, Wang X, Sun C-L et al (2008) Role of C. elegans TAT-1 protein in maintaining plasma membrane phosphatidylserine asymmetry. Science 320:528–531

    PubMed  CAS  Google Scholar 

  37. Dasgupta SK, Abdel-Monem H, Niravath P et al (2009) Lactadherin and clearance of platelet-derived microvesicles. Blood 113:1332–1339

    PubMed  CAS  Google Scholar 

  38. Epand RM, Stevenson C, Bruins R et al (1998) The chirality of phosphatidylserine and the activation of protein kinase C. Biochemistry 37:12068–12073

    PubMed  CAS  Google Scholar 

  39. Estaquier J, Vallette F, Vayssiere J-L, Mignotte B (2012) The mitochondrial pathways of apoptosis. Adv Exp Med Biol 942:157–183

    PubMed  CAS  Google Scholar 

  40. Fadok VA, Voelker DR, Campbell PA et al (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216

    PubMed  CAS  Google Scholar 

  41. Fairn GD, Hermansson M, Somerharju P, Grinstein S (2011) Phosphatidylserine is polarized and required for proper Cdc42 localization and for development of cell polarity. Nat Cell Biol 13:1424–1430

    PubMed  CAS  Google Scholar 

  42. Fairn GD, Schieber NL, Ariotti N et al (2011) High-resolution mapping reveals topologically distinct cellular pools of phosphatidylserine. J Cell Biol 194:257–275

    PubMed  CAS  Google Scholar 

  43. Finkielstein CV, Overduin M, Capelluto DGS (2006) Cell migration and signaling specificity is determined by the phosphatidylserine recognition motif of Rac1. J Biol Chem 281:27317–27326

    PubMed  CAS  Google Scholar 

  44. Frasch SC, Berry KZ, Fernandez-Boyanapalli R et al (2008) NADPH oxidase-dependent generation of lysophosphatidylserine enhances clearance of activated and dying neutrophils via G2A. J Biol Chem 283:33736–33749

    PubMed  CAS  Google Scholar 

  45. Frasch SC, Bratton DL (2012) Emerging roles for lysophosphatidylserine in resolution of inflammation. Prog Lipid Res 51:199–207

    PubMed  CAS  Google Scholar 

  46. Freyssinet J-M, Toti F (2010) Formation of procoagulant microparticles and properties. Thromb Res 125(Suppl 1):S46–S48

    PubMed  CAS  Google Scholar 

  47. Ghosh S, Strum JC, Sciorra VA et al (1996) Raf-1 kinase possesses distinct binding domains for phosphatidylserine and phosphatidic acid. Phosphatidic acid regulates the translocation of Raf-1 in 12-O-tetradecanoylphorbol-13-acetate-stimulated Madin-Darby canine kidney cells. J Biol Chem 271:8472–8480

    PubMed  CAS  Google Scholar 

  48. Ghosh S, Xie WQ, Quest AF et al (1994) The cysteine-rich region of raf-1 kinase contains zinc, translocates to liposomes, and is adjacent to a segment that binds GTP-ras. J Biol Chem 269:10000–10007

    PubMed  CAS  Google Scholar 

  49. Gilbert GE, Furie BC, Furie B (1990) Binding of human factor VIII to phospholipid vesicles. J Biol Chem 265:815–822

    PubMed  CAS  Google Scholar 

  50. Gilbert GE, Kaufman RJ, Arena AA et al (2002) Four hydrophobic amino acids of the factor VIII C2 domain are constituents of both the membrane-binding and von Willebrand factor-binding motifs. J Biol Chem 277:6374–6381

    PubMed  CAS  Google Scholar 

  51. Graham TR (2004) Flippases and vesicle-mediated protein transport. Trends Cell Biol 14:670–677

    PubMed  CAS  Google Scholar 

  52. Greenberg ME, Sun M, Zhang R et al (2006) Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. J Exp Med 203:2613–2625

    PubMed  CAS  Google Scholar 

  53. Hampton MB, Vanags DM, Pörn-Ares MI, Orrenius S (1996) Involvement of extracellular calcium in phosphatidylserine exposure during apoptosis. FEBS Lett 399:277–282

    PubMed  CAS  Google Scholar 

  54. Hanayama R, Tanaka M, Miwa K et al (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417:182–187

    PubMed  CAS  Google Scholar 

  55. Hancock JF, Magee AI, Childs JE, Marshall CJ (1989) All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 57:1167–1177

    PubMed  CAS  Google Scholar 

  56. Hancock JF, Paterson H, Marshall CJ (1990) A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell 63:133–139

    PubMed  CAS  Google Scholar 

  57. Heemskerk JW, Siljander P, Vuist WM et al (1999) Function of glycoprotein VI and integrin alpha2beta1 in the procoagulant response of single, collagen-adherent platelets. Thromb Haemost 81:782–792

    PubMed  CAS  Google Scholar 

  58. Heemskerk JWM, Bevers EM, Lindhout T (2002) Platelet activation and blood coagulation. Thromb Haemost 88:186–193

    PubMed  CAS  Google Scholar 

  59. Hekman M, Hamm H, Villar AV et al (2002) Associations of B- and C-Raf with cholesterol, phosphatidylserine, and lipid second messengers: preferential binding of Raf to artificial lipid rafts. J Biol Chem 277:24090–24102

    CAS  Google Scholar 

  60. Hicks AM, DeLong CJ, Thomas MJ et al (2006) Unique molecular signatures of glycerophospholipid species in different rat tissues analyzed by tandem mass spectrometry. Biochim Biophys Acta 1761:1022–1029

    PubMed  CAS  Google Scholar 

  61. Higgins JA, Dawson RM (1977) Asymmetry of the phospholipid bilayer of rat liver endoplasmic reticulum. Biochim Biophys Acta 470:342–356

    PubMed  CAS  Google Scholar 

  62. Hla T (2004) Prostaglandins & other lipid mediators: a new phase, a new team. Prostaglandins Other Lipid Mediat 73:1–2

    CAS  Google Scholar 

  63. Hobson JP, Rosenfeldt HM, Barak LS et al (2001) Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science 291:1800–1803

    PubMed  CAS  Google Scholar 

  64. Hoppe AD, Swanson JA (2004) Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol Biol Cell 15:3509–3519

    PubMed  CAS  Google Scholar 

  65. Hosono H, Aoki J, Nagai Y et al (2001) Phosphatidylserine-specific phospholipase A1 stimulates histamine release from rat peritoneal mast cells through production of 2-acyl-1-lysophosphatidylserine. J Biol Chem 276:29664–29670

    PubMed  CAS  Google Scholar 

  66. Hua Z, Fatheddin P, Graham TR (2002) An essential subfamily of Drs2p-related P-type ATPases is required for protein trafficking between Golgi complex and endosomal/vacuolar system. Mol Biol Cell 13:3162–3177

    PubMed  CAS  Google Scholar 

  67. Huang BX, Akbar M, Kevala K, Kim H-Y (2011) Phosphatidylserine is a critical modulator for Akt activation. J Cell Biol 192:979–992

    PubMed  CAS  Google Scholar 

  68. Huang M, Rigby AC, Morelli X et al (2003) Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins. Nat Struct Biol 10:751–756

    PubMed  CAS  Google Scholar 

  69. Jacquemin MG, Desqueper BG, Benhida A et al (1998) Mechanism and kinetics of factor VIII inactivation: study with an IgG4 monoclonal antibody derived from a hemophilia A patient with inhibitor. Blood 92:496–506

    PubMed  CAS  Google Scholar 

  70. Jo D-G, Jun J-I, Chang J-W et al (2004) Calcium binding of ARC mediates regulation of caspase 8 and cell death. Mol Cell Biol 24:9763–9770

    PubMed  CAS  Google Scholar 

  71. Johnson KR, Becker KP, Facchinetti MM et al (2002) PKC-dependent activation of sphingosine kinase 1 and translocation to the plasma membrane. Extracellular release of sphingosine-1-phosphate induced by phorbol 12-myristate 13-acetate (PMA). J Biol Chem 277:35257–35262

    PubMed  CAS  Google Scholar 

  72. Johnson LM, James KM, Chamberlain MD, Anderson DH (2005) Identification of key residues in the A-Raf kinase important for phosphoinositide lipid binding specificity. Biochemistry 44:3432–3440

    PubMed  CAS  Google Scholar 

  73. Jung EM, Lee T-J, Park J-W et al (2008) The novel phospholipase C activator, m-3M3FBS, induces apoptosis in tumor cells through caspase activation, down-regulation of XIAP and intracellular calcium signaling. Apoptosis 13:133–145

    PubMed  CAS  Google Scholar 

  74. Kay JG, Koivusalo M, Ma X et al (2012) Phosphatidylserine dynamics in cellular membranes. Mol Biol Cell 23:2198–2212

    PubMed  CAS  Google Scholar 

  75. Kim H-Y (2007) Novel metabolism of docosahexaenoic acid in neural cells. J Biol Chem 282:18661–18665

    PubMed  CAS  Google Scholar 

  76. Kim SW, Quinn-Allen MA, Camp JT et al (2000) Identification of functionally important amino acid residues within the C2-domain of human factor V using alanine-scanning mutagenesis. Biochemistry 39:1951–1958

    PubMed  CAS  Google Scholar 

  77. Knight CG, Morton LF, Onley DJ et al (1999) Collagen-platelet interaction: Gly-Pro-Hyp is uniquely specific for platelet Gp VI and mediates platelet activation by collagen. Cardiovasc Res 41:450–457

    PubMed  CAS  Google Scholar 

  78. Knight JD, Falke JJ (2009) Single-molecule fluorescence studies of a PH domain: new insights into the membrane docking reaction. Biophys J 96:566–582

    PubMed  CAS  Google Scholar 

  79. Kobayashi N, Karisola P, Peña-Cruz V et al (2007) TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27:927–940

    PubMed  CAS  Google Scholar 

  80. Koopman G, Reutelingsperger CP, Kuijten GA et al (1994) Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84:1415–1420

    PubMed  CAS  Google Scholar 

  81. Laude AJ, Prior IA (2008) Palmitoylation and localisation of RAS isoforms are modulated by the hypervariable linker domain. J Cell Sci 121:421–427

    PubMed  CAS  Google Scholar 

  82. Lee MJ, Thangada S, Claffey KP et al (1999) Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 99:301–312

    PubMed  CAS  Google Scholar 

  83. Lemke G, Burstyn-Cohen T (2010) TAM receptors and the clearance of apoptotic cells. Ann N Y Acad Sci 1209:23–29

    PubMed  CAS  Google Scholar 

  84. Leventis PA, Grinstein S (2010) The distribution and function of phosphatidylserine in cellular membranes. Annu Rev Biophys 39:407–427

    PubMed  CAS  Google Scholar 

  85. Lhermusier T, Chap H, Payrastre B (2011) Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome. J Thromb Haemost 9:1883–1891

    PubMed  CAS  Google Scholar 

  86. Lin L, Huai Q, Huang M et al (2007) Crystal structure of the bovine lactadherin C2 domain, a membrane binding motif, shows similarity to the C2 domains of factor V and factor VIII. J Mol Biol 371:717–724

    PubMed  CAS  Google Scholar 

  87. Lucas N, Cho W (2011) Phosphatidylserine binding is essential for plasma membrane recruitment and signaling function of 3-phosphoinositide dependent kinase-1. J Biol Chem 286(48):41265–41272

    PubMed  CAS  Google Scholar 

  88. Macedo-Ribeiro S, Bode W, Huber R et al (1999) Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature 402:434–439

    PubMed  CAS  Google Scholar 

  89. Mackler JM, Drummond JA, Loewen CA et al (2002) The C(2)B Ca(2+)-binding motif of synaptotagmin is required for synaptic transmission in vivo. Nature 418:340–344

    PubMed  CAS  Google Scholar 

  90. Makide K, Kitamura H, Sato Y et al (2009) Emerging lysophospholipid mediators, lysophosphatidylserine, lysophosphatidylthreonine, lysophosphatidylethanolamine and lysophosphatidylglycerol. Prostaglandins Other Lipid Mediat 89:135–139

    PubMed  CAS  Google Scholar 

  91. Mapes J, Chen Y-Z, Kim A et al (2012) CED-1, CED-7, and TTR-52 regulate surface phosphatidylserine expression on apoptotic and phagocytic cells. Curr Biol 22(14):1267–1275

    PubMed  CAS  Google Scholar 

  92. Marinetti G, Love R (1976) Differential reaction of cell membrane phospholipids and proteins with chemical probes. Chem Phys Lipids 16:239–254

    PubMed  CAS  Google Scholar 

  93. Martin OC, Pagano RE (1987) Transbilayer movement of fluorescent analogs of phosphatidylserine and phosphatidylethanolamine at the plasma membrane of cultured cells. Evidence for a protein-mediated and ATP-dependent process(es). J Biol Chem 262:5890–5898

    PubMed  CAS  Google Scholar 

  94. Martin SJ, Finucane DM, Amarante-Mendes GP et al (1996) Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity. J Biol Chem 271:28753–28756

    PubMed  CAS  Google Scholar 

  95. Martin TW, Lagunoff D (1979) Interactions of lysophospholipids and mast cells. Nature 279:250–252

    PubMed  CAS  Google Scholar 

  96. Mattson MP, Chan SL (2003) Calcium orchestrates apoptosis. Nat Cell Biol 5:1041–1043

    PubMed  CAS  Google Scholar 

  97. McPherson RA, Harding A, Roy S et al (1999) Interactions of c-Raf-1 with phosphatidylserine and 14-3-3. Oncogene 18:3862–3869

    PubMed  CAS  Google Scholar 

  98. Meers P, Mealy T (1993) Calcium-dependent annexin V binding to phospholipids: stoichiometry, specificity, and the role of negative charge. Biochemistry 32:11711–11721

    PubMed  CAS  Google Scholar 

  99. Meers P, Mealy T (1994) Phospholipid determinants for annexin V binding sites and the role of tryptophan 187. Biochemistry 33:5829–5837

    PubMed  CAS  Google Scholar 

  100. Michaelson D, Silletti J, Murphy G et al (2001) Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J Cell Biol 152:111–126

    PubMed  CAS  Google Scholar 

  101. Mirnikjoo B, Balasubramanian K, Schroit AJ (2008) Mobilization of lysosomal calcium regulates the externalization of phosphatidylserine during apoptosis. J Biol Chem 284:6918–6923

    Google Scholar 

  102. Mirnikjoo B, Balasubramanian K, Schroit AJ (2009) Suicidal membrane repair regulates phosphatidylserine externalization during apoptosis. J Biol Chem 284:22512–22516

    PubMed  CAS  Google Scholar 

  103. Mott HR, Carpenter JW, Zhong S et al (1996) The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site. Proc Natl Acad Sci U S A 93:8312–8317

    PubMed  CAS  Google Scholar 

  104. Mukherjee S, Chattopadhyay A, Samanta A, Soujanya T (1994) Dipole moment change of NBD group upon excitation studied using solvatochromic and quantum chemical approaches: implications in membrane research. J Phys Chem 98:2809–2812

    CAS  Google Scholar 

  105. Muñoz-Pinedo C (2012) Signaling pathways that regulate life and cell death: evolution of apoptosis in the context of self-defense. Adv Exp Med Biol 738:124–143

    PubMed  Google Scholar 

  106. Murata-Kamiya N, Kikuchi K, Hayashi T et al (2010) Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein. Cell Host Microbe 7:399–411

    PubMed  CAS  Google Scholar 

  107. Nagata S, Hanayama R, Kawane K (2010) Autoimmunity and the clearance of dead cells. Cell 140:619–630

    PubMed  CAS  Google Scholar 

  108. Nakano T, Ishimoto Y, Kishino J et al (1997) Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J Biol Chem 272:29411–29414

    PubMed  CAS  Google Scholar 

  109. Natarajan P, Wang J, Hua Z, Graham TR (2004) Drs2p-coupled aminophospholipid translocase activity in yeast Golgi membranes and relationship to in vivo function. Proc Natl Acad Sci U S A 101:10614–10619

    PubMed  CAS  Google Scholar 

  110. Navarro-Lérida I, Sánchez-Perales S, Calvo M et al (2012) A palmitoylation switch mechanism regulates Rac1 function and membrane organization. EMBO J 31:534–551

    PubMed  Google Scholar 

  111. Needham D, Zhelev DV (1995) Lysolipid exchange with lipid vesicle membranes. Ann Biomed Eng 23:287–298

    PubMed  CAS  Google Scholar 

  112. Nikawa JI, Yamashita S (1981) Characterization of phosphatidylserine synthase from Saccharomyces cerevisiae and a mutant defective in the enzyme. Biochim Biophys Acta 665:420–426

    PubMed  CAS  Google Scholar 

  113. Okeley NM, Gelb MH (2004) A designed probe for acidic phospholipids reveals the unique enriched anionic character of the cytosolic face of the mammalian plasma membrane. J Biol Chem 279:21833–21840

    PubMed  CAS  Google Scholar 

  114. Padilla-López S, Langager D, Chan C-H, Pearce DA (2012) BTN1, the Saccharomyces cerevisiae homolog to the human Batten disease gene, is involved in phospholipid distribution. Dis Model Mech 5:191–199

    PubMed  Google Scholar 

  115. Park D, Tosello-Trampont A-C, Elliott MR et al (2007) BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450:430–434

    PubMed  CAS  Google Scholar 

  116. Park KS, Lee H-Y, Kim M-K et al (2006) Lysophosphatidylserine stimulates L2071 mouse fibroblast chemotactic migration via a process involving pertussis toxin-sensitive trimeric G-proteins. Mol Pharmacol 69:1066–1073

    PubMed  CAS  Google Scholar 

  117. Park S-Y, Jung M-Y, Kim H-J et al (2008) Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ 15:192–201

    PubMed  CAS  Google Scholar 

  118. Park S-Y, Kim S-Y, Jung M-Y et al (2008) Epidermal growth factor-like domain repeat of stabilin-2 recognizes phosphatidylserine during cell corpse clearance. Mol Cell Biol 28:5288–5298

    PubMed  CAS  Google Scholar 

  119. Paulusma CC, Elferink RPJO (2010) P4 ATPases–the physiological relevance of lipid flipping transporters. FEBS Lett 584:2708–2716

    PubMed  CAS  Google Scholar 

  120. Pitson SM, Moretti PAB, Zebol JR et al (2003) Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J 22:5491–5500

    PubMed  CAS  Google Scholar 

  121. Pomorski T, Lombardi R, Riezman H et al (2003) Drs2p-related P-type ATPases Dnf1p and Dnf2p are required for phospholipid translocation across the yeast plasma membrane and serve a role in endocytosis. Mol Biol Cell 14:1240–1254

    PubMed  CAS  Google Scholar 

  122. Pratt KP, Shen BW, Takeshima K et al (1999) Structure of the C2 domain of human factor VIII at 1.5 A resolution. Nature 402:439–442

    PubMed  CAS  Google Scholar 

  123. Ravichandran KS (2011) Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35:445–455

    PubMed  CAS  Google Scholar 

  124. Reverter JC, Béguin S, Kessels H et al (1996) Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and “clinical restenosis”. J Clin Invest 98:863–874

    PubMed  CAS  Google Scholar 

  125. Rosing J, Bevers EM, Comfurius P et al (1985) Impaired factor X and prothrombin activation associated with decreased phospholipid exposure in platelets from a patient with a bleeding disorder. Blood 65:1557–1561

    PubMed  CAS  Google Scholar 

  126. Rosing J, Tans G, Govers-Riemslag JW et al (1980) The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem 255:274–283

    PubMed  CAS  Google Scholar 

  127. Rosse C, Linch M, Kermorgant S et al (2010) PKC and the control of localized signal dynamics. Nat Rev Mol Cell Biol 11:103–112

    PubMed  CAS  Google Scholar 

  128. Sahu SK, Gummadi SN, Manoj N, Aradhyam GK (2007) Phospholipid scramblases: an overview. Arch Biochem Biophys 462:103–114

    PubMed  CAS  Google Scholar 

  129. Saito K, Nishijima M, Kuge O (1998) Genetic evidence that phosphatidylserine synthase II catalyzes the conversion of phosphatidylethanolamine to phosphatidylserine in Chinese hamster ovary cells. J Biol Chem 273:17199–17205

    PubMed  CAS  Google Scholar 

  130. Santiago C, Ballesteros A, Martínez-Muñoz L et al (2007) Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds. Immunity 27:941–951

    PubMed  CAS  Google Scholar 

  131. Sato T, Aoki J, Nagai Y et al (1997) Serine phospholipid-specific phospholipase A that is secreted from activated platelets. A new member of the lipase family. J Biol Chem 272:2192–2198

    PubMed  CAS  Google Scholar 

  132. Schick PK, Kurica KB, Chacko GK (1976) Location of phosphatidylethanolamine and phosphatidylserine in the human platelet plasma membrane. J Clin Invest 57:1221–1226

    PubMed  CAS  Google Scholar 

  133. Schoenwaelder SM, Yuan Y, Josefsson EC et al (2009) Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood 114:663–666

    PubMed  CAS  Google Scholar 

  134. Sebastian TT, Baldridge RD, Xu P, Graham TR (2011) Phospholipid flippases: building asymmetric membranes and transport vesicles. Biochim Biophys Acta 1821(8):1068–1077

    PubMed  Google Scholar 

  135. Seigneuret M, Devaux PF (1984) ATP-dependent asymmetric distribution of spin-labeled phospholipids in the erythrocyte membrane: relation to shape changes. Proc Natl Acad Sci U S A 81:3751–3755

    PubMed  CAS  Google Scholar 

  136. Shao C, Novakovic VA, Head JF et al (2008) Crystal structure of lactadherin C2 domain at 1.7A resolution with mutational and computational analyses of its membrane-binding motif. J Biol Chem 283:7230–7241

    PubMed  CAS  Google Scholar 

  137. Shi J, Gilbert GE (2003) Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites. Blood 101:2628–2636

    PubMed  CAS  Google Scholar 

  138. Shi J, Heegaard CW, Rasmussen JT, Gilbert GE (2004) Lactadherin binds selectively to membranes containing phosphatidyl-L-serine and increased curvature. Biochim Biophys Acta 1667:82–90

    PubMed  CAS  Google Scholar 

  139. Shi J, Shi Y, Waehrens LN et al (2006) Lactadherin detects early phosphatidylserine exposure on immortalized leukemia cells undergoing programmed cell death. Cytometry 69:1193–1201

    PubMed  Google Scholar 

  140. Shiao YJ, Balcerzak B, Vance JE (1998) A mitochondrial membrane protein is required for translocation of phosphatidylserine from mitochondria-associated membranes to mitochondria. Biochem J 331 (Pt 1):217–223

    PubMed  CAS  Google Scholar 

  141. Sigal CT, Zhou W, Buser CA et al (1994) Amino-terminal basic residues of Src mediate membrane binding through electrostatic interaction with acidic phospholipids. Proc Natl Acad Sci U S A 91:12253–12257

    PubMed  CAS  Google Scholar 

  142. Smith GA, Hesketh TR, Plumb RW, Metcalfe JC (1979) The exogenous lipid requirement for histamine release from rat peritoneal mast cells stimulated by concanavalin A. FEBS Lett 105:58–62

    PubMed  CAS  Google Scholar 

  143. Sperka-Gottlieb CD, Hermetter A, Paltauf F, Daum G (1988) Lipid topology and physical properties of the outer mitochondrial membrane of the yeast, Saccharomyces cerevisiae. Biochim Biophys Acta 946:227–234

    PubMed  CAS  Google Scholar 

  144. Stahelin RV, Hwang JH, Kim J-H et al (2005) The mechanism of membrane targeting of human sphingosine kinase 1. J Biol Chem 280:43030–43038

    PubMed  CAS  Google Scholar 

  145. Steenbergen R, Nanowski TS, Beigneux A et al (2005) Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects. J Biol Chem 280:40032–40040

    PubMed  CAS  Google Scholar 

  146. Stein A, Radhakrishnan A, Riedel D et al (2007) Synaptotagmin activates membrane fusion through a Ca2+−dependent trans interaction with phospholipids. Nat Struct Mol Biol 14:904–911

    PubMed  CAS  Google Scholar 

  147. Stevens CF, Sullivan JM (2003) The synaptotagmin C2A domain is part of the calcium sensor controlling fast synaptic transmission. Neuron 39:299–308

    PubMed  CAS  Google Scholar 

  148. Sutton RB, Sprang SR (1998) Structure of the protein kinase Cbeta phospholipid-binding C2 domain complexed with Ca2+. Structure 6:1395–1405

    PubMed  CAS  Google Scholar 

  149. Suzuki J, Umeda M, Sims PJ, Nagata S (2010) Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468:834–838

    PubMed  CAS  Google Scholar 

  150. Südhof TC (2002) Synaptotagmins: why so many? J Biol Chem 277:7629–7632

    PubMed  Google Scholar 

  151. Swairjo MA, Concha NO, Kaetzel MA et al (1995) Ca(2+)-bridging mechanism and phospholipid head group recognition in the membrane-binding protein annexin V. Nat Struct Biol 2:968–974

    PubMed  CAS  Google Scholar 

  152. Takai Y, Kishimoto A, Iwasa Y et al (1979) Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipids. J Biol Chem 254:3692–3695

    PubMed  CAS  Google Scholar 

  153. Takai Y, Kishimoto A, Kikkawa U et al (1979) Unsaturated diacylglycerol as a possible messenger for the activation of calcium-activated, phospholipid-dependent protein kinase system. Biochem Biophys Res Commun 91:1218–1224

    PubMed  CAS  Google Scholar 

  154. Tang X, Halleck MS, Schlegel RA, Williamson P (1996) A subfamily of P-type ATPases with aminophospholipid transporting activity. Science 272:1495–1497

    PubMed  CAS  Google Scholar 

  155. Tyurin VA, Tyurina YY, Kochanek PM et al (2008) Oxidative lipidomics of programmed cell death. Methods Enzymol 442:375–393

    PubMed  CAS  Google Scholar 

  156. Uchida Y, Hasegawa J, Chinnapen D et al (2011) Intracellular phosphatidylserine is essential for retrograde membrane traffic through endosomes. Proc Natl Acad Sci U S A 108:15846–15851

    PubMed  CAS  Google Scholar 

  157. Udell CM, Rajakulendran T, Sicheri F, Therrien M (2011) Mechanistic principles of RAF kinase signaling. Cell Mol Life Sci 68:553–565

    PubMed  CAS  Google Scholar 

  158. Vale MG (1977) Localization of the amino phospholipids in sarcoplasmic reticulum membranes revealed by trinitrobenzenesulfonate and fluorodinitrobenzene. Biochim Biophys Acta 471:39–48

    PubMed  CAS  Google Scholar 

  159. van de Waart P, Bruls H, Hemker HC, Lindhout T (1983) Interaction of bovine blood clotting factor Va and its subunits with phospholipid vesicles. Biochemistry 22:2427–2432

    PubMed  Google Scholar 

  160. van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112–124

    PubMed  Google Scholar 

  161. Vance JE (2008) Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res 49:1377–1387

    PubMed  CAS  Google Scholar 

  162. Vance JE (2003) Molecular and cell biology of phosphatidylserine and phosphatidylethanolamine metabolism. Prog Nucleic Acid Res Mol Biol 75:69–111

    PubMed  CAS  Google Scholar 

  163. Vance JE, Steenbergen R (2005) Metabolism and functions of phosphatidylserine. Prog Lipid Res 44:207–234

    PubMed  CAS  Google Scholar 

  164. Verdaguer N, Corbalan-Garcia S, Ochoa WF et al (1999) Ca(2+) bridges the C2 membrane-binding domain of protein kinase Calpha directly to phosphatidylserine. EMBO J 18:6329–6338

    PubMed  CAS  Google Scholar 

  165. Weiss HJ, Vicic WJ, Lages BA, Rogers J (1979) Isolated deficiency of platelet procoagulant activity. Am J Med 67:206–213

    PubMed  CAS  Google Scholar 

  166. Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118:843–846

    PubMed  CAS  Google Scholar 

  167. Williamson P, Bevers EM, Smeets EF et al (1995) Continuous analysis of the mechanism of activated transbilayer lipid movement in platelets. Biochemistry 34:10448–10455

    PubMed  CAS  Google Scholar 

  168. Williamson P, Christie A, Kohlin T et al (2001) Phospholipid scramblase activation pathways in lymphocytes. Biochemistry 40:8065–8072

    PubMed  CAS  Google Scholar 

  169. Williamson P, Schlegel RA (2002) Transbilayer phospholipid movement and the clearance of apoptotic cells. Biochim Biophys Acta 1585:53–63

    PubMed  CAS  Google Scholar 

  170. Yamaguchi H, Takagi J, Miyamae T et al (2008) Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus erythematosus. J Leukoc Biol 83:1300–1307

    PubMed  CAS  Google Scholar 

  171. Yáñez M, Gil-Longo J, Campos-Toimil M (2012) Calcium binding proteins. Adv Exp Med Biol 740:461–482

    PubMed  Google Scholar 

  172. Yeung T, Gilbert GE, Shi J et al (2008) Membrane phosphatidylserine regulates surface charge and protein localization. Science 319:210–213

    PubMed  CAS  Google Scholar 

  173. Yeung T, Heit B, Dubuisson J-F et al (2009) Contribution of phosphatidylserine to membrane surface charge and protein targeting during phagosome maturation. J Cell Biol 185:917–928

    PubMed  CAS  Google Scholar 

  174. Yeung T, Terebiznik M, Yu L et al (2006) Receptor activation alters inner surface potential during phagocytosis. Science 313:347–351

    PubMed  CAS  Google Scholar 

  175. Zhang Z, Hui E, Chapman ER, Jackson MB (2009) Phosphatidylserine regulation of Ca2+−triggered exocytosis and fusion pores in PC12 cells. Mol Biol Cell 20:5086–5095

    PubMed  CAS  Google Scholar 

  176. Züllig S, Neukomm LJ, Jovanovic M et al (2007) Aminophospholipid translocase TAT-1 promotes phosphatidylserine exposure during C. elegans apoptosis. Curr Biol 17:994–999

    PubMed  Google Scholar 

  177. Zwaal RF, Comfurius P, van Deenen LL (1977) Membrane asymmetry and blood coagulation. Nature 268:358–360

    PubMed  CAS  Google Scholar 

  178. Zwaal RFA, Comfurius P, Bevers EM (2005) Surface exposure of phosphatidylserine in pathological cells. Cell Mol Life Sci 62:971–988

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Jason G. Kay & Sergio Grinstein

Authors
  1. Jason G. Kay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sergio Grinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sergio Grinstein .

Editor information

Editors and Affiliations

  1. , Biological Sciences, Virginia Tech, Kraft Drive 1981, Blacksburg, 24061, Virginia, USA

    Daniel G.S. Capelluto

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Kay, J.G., Grinstein, S. (2013). Phosphatidylserine-Mediated Cellular Signaling. In: Capelluto, D. (eds) Lipid-mediated Protein Signaling. Advances in Experimental Medicine and Biology, vol 991. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6331-9_10

Download citation

Publish with us

Policies and ethics

Search

Navigation