PtdIns(4,5)P2-Mediated Cell Signaling: Emerging Principles and PTEN as a Paradigm for Regulatory Mechanism

  • Arne Gericke
  • Nicholas R. Leslie
  • Mathias Lösche
  • Alonzo H. RossEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 991)


PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) is a relatively common anionic lipid that regulates cellular functions by multiple mechanisms. Hydrolysis of PtdIns(4,5)P2 by phospholipase C yields inositol trisphosphate and diacylglycerol. Phosphorylation by phosphoinositide 3-kinase yields PtdIns(3,4,5)P3, which is a potent signal for survival and proliferation. Also, PtdIns(4,5)P2 can bind directly to integral and peripheral membrane proteins. As an example of regulation by PtdIns(4,5)P2, we discuss phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in detail. PTEN is an important tumor suppressor and hydrolyzes PtdIns(3,4,5)P3. PtdIns(4,5)P2 enhances PTEN association with the plasma membrane and activates its phosphatase activity. This is a critical regulatory mechanism, but a detailed description of this process from a structural point of view is lacking. The disordered lipid bilayer environment hinders structural determinations of membrane-bound PTEN. A new method to analyze membrane-bound protein measures neutron reflectivity for proteins bound to tethered phospholipid membranes. These methods allow determination of the orientation and shape of membrane-bound proteins. In combination with molecular dynamics simulations, these studies will provide crucial structural information that can serve as a foundation for our understanding of PTEN regulation in normal and pathological processes.


Phosphoinositide Phosphatidylinositol 4,5-bisphosphate Lipid membrane PTEN Phosphatase 



We thank Marie-Claire Daou for PTEN protein preparation, and Drs. Siddharth Shenoy, Prabhanshu Shekhar, Frank Heinrich, and Hirsh Nanda for conducting the neutron scattering and MD simulation work and for stimulating discussions and Drs. David Vanderah and Gintaras Valincius for a fruitful collaborations on the design and optimization of tethered bilayer sample formats. This work was supported by the NIH (P01 AG032131, R01 GM101647 and R01 NS021716), NSF (CHEM 442288) and the Department of Commerce (70NANB8H8009 and 70NANB11H8139). Beamtime at the NIST Center for Neutron Research and computational resources at the NIH (, the Extreme Science and Engineering Discovery Environment (XSEDE), supported by the NSF (OCI-105357), with computations performed at the NICS ( and the Pittsburgh Supercomputing Center (BIO110004P), are gratefully acknowledged.


  1. 1.
    Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657PubMedGoogle Scholar
  2. 2.
    Foukas LC, Berenjeno IM, Gray A, Khwaja A, Vanhaesebroeck B (2010) Activity of any class IA PI3K isoform can sustain cell proliferation and survival. Proc Natl Acad Sci USA 107:11381–11386PubMedGoogle Scholar
  3. 3.
    Leslie NR, Downes CP (2002) PTEN: the down side of PI 3-kinase signalling. Cell Signal 14:285–295PubMedGoogle Scholar
  4. 4.
    van den Bout I, Divecha N (2009) PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions. J Cell Sci 122:3837–3850PubMedGoogle Scholar
  5. 5.
    Clarke JH, Irvine RF (2012) The activity, evolution and association of phosphatidylinositol 5-phosphate 4-kinases. Adv Enzyme Regul 52:40–45Google Scholar
  6. 6.
    Ramel D, Lagarrigue F, Pons V, Mounier J, Dupuis-Coronas S, Chicanne G, Sansonetti PJ, Gaits-Iacovoni F, Tronchère H, Payrastre B (2011) Shigella flexneri infection generates the lipid PI5P to alter endocytosis and prevent termination of EGFR signaling. Sci Signal 4:ra61PubMedGoogle Scholar
  7. 7.
    Doughman RL, Firestone AJ, Wojtasiak ML, Bunce MW, Anderson RA (2003) Membrane ruffling requires coordination between type Iα phosphatidylinositol phosphate kinase and Rac signaling. J Biol Chem 278:23036–23045PubMedGoogle Scholar
  8. 8.
    Giudici ML, Lee K, Lim R, Irvine RF (2006) The intracellular localisation and mobility of type Iγ phosphatidylinositol 4P 5-kinase splice variants. FEBS Lett 580:6933–6937PubMedGoogle Scholar
  9. 9.
    Ling K, Bairstow SF, Carbonara C, Turbin DA, Huntsman DG, Anderson RA (2007) Type Iγ phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with μ1B adaptin. J Cell Biol 176:343–353PubMedGoogle Scholar
  10. 10.
    Hammond GRV, Schiavo G, Irvine RF (2009) Immunocytochemical techniques reveal multiple, distinct cellular pools of PtdIns4P and PtdIns(4,5)P2. Biochem J 422:23–35PubMedGoogle Scholar
  11. 11.
    Szentpetery Z, Balla A, Kim YJ, Lemmon MA, Balla T (2009) Live cell imaging with protein domains capable of recognizing phosphatidylinositol 4,5-bisphosphate; a comparative study. BMC Cell Biol 10:67PubMedGoogle Scholar
  12. 12.
    Watt SA, Kular G, Fleming IN, Downes CP, Lucocq JM (2002) Subcellular localization of phosphatidylinositol 4,5-bisphosphate using the pleckstrin homology domain of phospholipase C δ1. Biochem J 363:657–666PubMedGoogle Scholar
  13. 13.
    Nakatsu F, Perera RM, Lucast L, Zoncu R, Domin J, Gertler FB, Toomre D, De Camilli P (2010) The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics. J Cell Biol 190:307–315PubMedGoogle Scholar
  14. 14.
    Vicinanza M, Di Campli A, Polishchuk E, Santoro M, Di Tullio G, Godi A, Levtchenko E, De Leo MG, Polishchuk R, Sandoval L, Marzolo M-P, De Matteis MA (2011) OCRL controls trafficking through early endosomes via PtdIns4,5P2-dependent regulation of endosomal actin. EMBO J 30:4970–4985PubMedGoogle Scholar
  15. 15.
    James DJ, Khodthong C, Kowalchyk JA, Martin TFJ (2008) Phosphatidylinositol 4,5-bisphosphate regulates SNARE-dependent membrane fusion. J Cell Biol 182:355–366PubMedGoogle Scholar
  16. 16.
    Lingwood D, Simons K (2010) Lipid rafts as a membrane-organizing principle. Science 327:46–50PubMedGoogle Scholar
  17. 17.
    van den Bogaart G, Meyenberg K, Risselada HJ, Amin H, Willig KI, Hubrich BE, Dier M, Hell SW, Grubmüller H, Diederichsen U, Jahn R (2011) Membrane protein sequestering by ionic protein-lipid interactions. Nature 479:552–555PubMedGoogle Scholar
  18. 18.
    Barlow CA, Laishram RS, Anderson RA (2010) Nuclear phosphoinositides: a signaling enigma wrapped in a compartmental conundrum. Trends Cell Biol 20:25–35PubMedGoogle Scholar
  19. 19.
    Cocco L, Gilmour RS, Ognibene A, Letcher AJ, Manzoli FA, Irvine RF (1987) Synthesis of polyphosphoinositides in nuclei of friend cells. Evidence for polyphosphoinositide metabolism inside the nucleus which changes with cell differentiation. Biochem J 248:765–770PubMedGoogle Scholar
  20. 20.
    Cocco L, Manzoli L, Barnabei O, Martelli AM (2004) Significance of subnuclear localization of key players of inositol lipid cycle. Adv Enzyme Regul 44:51–60PubMedGoogle Scholar
  21. 21.
    Irvine RF (2003) Nuclear lipid signalling. Nat Rev Mol Cell Biol 4:349–360PubMedGoogle Scholar
  22. 22.
    Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, Myszka DG, Shapiro L (2001) G-protein signaling through tubby proteins. Science 292:2041–2050PubMedGoogle Scholar
  23. 23.
    Hirose K, Kadowaki S, Tanabe M, Takeshima H, Iino M (1999) Spatiotemporal dynamics of inositol 1,4,5-trisphosphate that underlies complex Ca2+ mobilization patterns. Science 284:1527–1530PubMedGoogle Scholar
  24. 24.
    Heo WD, Inoue T, Park WS, Kim ML, Park BO, Wandless TJ, Meyer T (2006) PI(3,4,5)P3 and PI(4,5)P2 lipids target proteins with polybasic clusters to the plasma membrane. Science 314:1458–1461PubMedGoogle Scholar
  25. 25.
    Yeung T, Terebiznik M, Yu L, Silvius J, Abidi WM, Philips M, Levine T, Kapus A, Grinstein S (2006) Receptor activation alters inner surface potential during phagocytosis. Science 313:347–351PubMedGoogle Scholar
  26. 26.
    Campbell RB, Liu F, Ross AH (2003) Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate. J Biol Chem 278:33617–33620PubMedGoogle Scholar
  27. 27.
    Falkenburger BH, Jensen JB, Dickson EJ, Suh B-C, Hille B (2010) Phosphoinositides: lipid regulators of membrane proteins. J Physiol (Lond) 588:3179–3185Google Scholar
  28. 28.
    Hansen SB, Tao X, MacKinnon R (2011) Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2. Nature 477:495–498PubMedGoogle Scholar
  29. 29.
    Redfern RE, Redfern DA, Furgason ML, Munson M, Ross AH, Gericke A (2008) PTEN phosphatase selectively binds phosphoinositides and undergoes structural changes. Biochemistry 47:2162–2171PubMedGoogle Scholar
  30. 30.
    Fievet BT, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D, Arpin M (2004) Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J Cell Biol 164:653–659PubMedGoogle Scholar
  31. 31.
    Leslie NR, Batty IH, Maccario H, Davidson L, Downes CP (2008) Understanding PTEN regulation: PIP2, polarity and protein stability. Oncogene 27:5464–5476PubMedGoogle Scholar
  32. 32.
    Katan M (1998) Families of phosphoinositide-specific phospholipase C: structure and function. Biochim Biophys Acta 1436:5–17PubMedGoogle Scholar
  33. 33.
    Oancea E, Meyer T (1998) Protein kinase C as a molecular machine for decoding calcium and diacylglycerol signals. Cell 95:307–318PubMedGoogle Scholar
  34. 34.
    Nakamura Y, Fukami K (2009) Roles of phospholipase C isozymes in organogenesis and embryonic development. Physiology (Bethesda) 24:332–341Google Scholar
  35. 35.
    Batty IH, Downes CP (1996) Thrombin receptors modulate insulin-stimulated phosphatidylinositol 3,4,5-trisphosphate accumulation in 1321N1 astrocytoma cells. Biochem J 317(Pt 2):347–351PubMedGoogle Scholar
  36. 36.
    Gamper N, Shapiro MS (2007) Target-specific PIP2 signalling: how might it work? J Physiol (Lond) 582:967–975Google Scholar
  37. 37.
    Vanhaesebroeck B, Stephens L, Hawkins P (2012) PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol 13:195–203PubMedGoogle Scholar
  38. 38.
    Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27:5497–5510PubMedGoogle Scholar
  39. 39.
    Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378PubMedGoogle Scholar
  40. 40.
    McConnachie G, Pass I, Walker SM, Downes CP (2003) Interfacial kinetic analysis of the tumour suppressor phosphatase, PTEN: evidence for activation by anionic phospholipids. Biochem J 371:947–955PubMedGoogle Scholar
  41. 41.
    Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927PubMedGoogle Scholar
  42. 42.
    Stocker H, Andjelkovic M, Oldham S, Laffargue M, Wymann MP, Hemmings BA, Hafen E (2002) Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science 295:2088–2091PubMedGoogle Scholar
  43. 43.
    Bayascas JR, Leslie NR, Parsons R, Fleming S, Alessi DR (2005) Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN+/− mice. Curr Biol 15:1839–1846PubMedGoogle Scholar
  44. 44.
    Zhang XC, Piccini A, Myers MP, Van Aelst L, Tonks NK (2012) Functional analysis of the protein phosphatase activity of PTEN. Biochem J 444:457–464PubMedGoogle Scholar
  45. 45.
    Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi PP, Pavletich NP (1999) Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99:323–334PubMedGoogle Scholar
  46. 46.
    Iijima M, Huang YE, Luo HR, Vazquez F, Devreotes PN (2004) Novel mechanism of PTEN regulation by its phosphatidylinositol 4,5-bisphosphate binding motif is critical for chemotaxis. J Biol Chem 279:16606–16613PubMedGoogle Scholar
  47. 47.
    Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR (2001) Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem 276:48627–48630PubMedGoogle Scholar
  48. 48.
    Odriozola L, Singh G, Hoang T, Chan AM (2007) Regulation of PTEN activity by its carboxyl-terminal autoinhibitory domain. J Biol Chem 282:23306–23315PubMedGoogle Scholar
  49. 49.
    Molina JR, Agarwal NK, Morales FC, Hayashi Y, Aldape KD, Cote G, Georgescu M-M (2012) PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma. Oncogene 31:1264–1274PubMedGoogle Scholar
  50. 50.
    Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13:283–296PubMedGoogle Scholar
  51. 51.
    Simpson L, Parsons R (2001) PTEN: life as a tumor suppressor. Exp Cell Res 264:29–41PubMedGoogle Scholar
  52. 52.
    Goffin A, Hoefsloot LH, Bosgoed E, Swillen A, Fryns JP (2001) PTEN mutation in a family with Cowden syndrome and autism. Am J Med Genet 105:521–524PubMedGoogle Scholar
  53. 53.
    Butler MG, Dasouki MJ, Zhou X-P, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 42:318–321PubMedGoogle Scholar
  54. 54.
    Boccone L, Dessì V, Zappu A, Piga S, Piludu MB, Rais M, Massidda C, De Virgiliis S, Cao A, Loudianos G (2006) Bannayan-Riley-Ruvalcaba syndrome with reactive nodular lymphoid hyperplasia and autism and a PTEN mutation. Am J Med Genet A 140:1965–1969PubMedGoogle Scholar
  55. 55.
    Herman GE, Butter E, Enrile B, Pastore M, Prior TW, Sommer A (2007) Increasing knowledge of PTEN germline mutations: two additional patients with autism and macrocephaly. Am J Med Genet A 143:589–593PubMedGoogle Scholar
  56. 56.
    Orrico A, Galli L, Buoni S, Orsi A, Vonella G, Sorrentino V (2009) Novel PTEN mutations in neurodevelopmental disorders and macrocephaly. Clin Genet 75:195–198PubMedGoogle Scholar
  57. 57.
    Stein MT, Elias ER, Saenz M, Pickler L, Reynolds A (2010) Autistic spectrum disorder in a 9-year-old girl with macrocephaly. J Dev Behav Pediatr 31:632–634PubMedGoogle Scholar
  58. 58.
    McBride KL, Varga EA, Pastore MT, Prior TW, Manickam K, Atkin JF, Herman GE (2010) Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. Autism Res 3:137–141PubMedGoogle Scholar
  59. 59.
    Gupta R, Ting JTL, Sokolov LN, Johnson SA, Luan S (2002) A tumor suppressor homolog, AtPTEN1, is essential for pollen development in Arabidopsis. Plant Cell 14:2495–2507PubMedGoogle Scholar
  60. 60.
    Janetopoulos C, Borleis J, Vazquez F, Iijima M, Devreotes PN (2005) Temporal and spatial regulation of phosphoinositide signaling mediates cytokinesis. Dev Cell 8:467–477PubMedGoogle Scholar
  61. 61.
    Mutti NS, Wang Y, Kaftanoglu O, Amdam GV (2011) Honey bee PTEN – description, developmental knockdown, and tissue-specific expression of splice-variants correlated with alternative social phenotypes. PLoS One 6:e22195PubMedGoogle Scholar
  62. 62.
    Ogg S, Ruvkun G (1998) The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol Cell 2:887–893PubMedGoogle Scholar
  63. 63.
    Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP (1999) Impaired Fas response and autoimmunity in Pten+/− mice. Science 285:2122–2125PubMedGoogle Scholar
  64. 64.
    Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di Cristofano A, Xiao A, Khoo AS, Roy-Burman P, Greenberg NM, Van Dyke T, Cordon-Cardo C, Pandolfi PP (2003) Pten dose dictates cancer progression in the prostate. PLoS Biol 1:385–396Google Scholar
  65. 65.
    Eng C, Murday V, Seal S, Mohammed S, Hodgson SV, Chaudary MA, Fentiman IS, Ponder BA, Eeles RA (1994) Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy? J Med Genet 31:458–461PubMedGoogle Scholar
  66. 66.
    Vazquez F, Ramaswamy S, Nakamura N, Sellers W (2000) Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol 20:5010–5018PubMedGoogle Scholar
  67. 67.
    Vazquez F, Matsuoka S, Sellers WR, Yanagida T, Ueda M, Devreotes PN (2006) Tumor suppressor PTEN acts through dynamic interaction with the plasma membrane. Proc Natl Acad Sci USA 103:3633–3638PubMedGoogle Scholar
  68. 68.
    Rahdar M, Inoue T, Meyer T, Zhang J, Vazquez F, Devreotes PN (2009) A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. Proc Natl Acad Sci USA 106:480–485PubMedGoogle Scholar
  69. 69.
    Das S, Dixon J, Cho W (2003) Membrane-binding and activation mechanism of PTEN. Proc Natl Acad Sci USA 100:7491–7496PubMedGoogle Scholar
  70. 70.
    Walker S, Leslie N, Perera N, Batty I, Downes C (2004) The tumour-suppressor function of PTEN requires an N-terminal lipid-binding motif. Biochem J 379:301–307PubMedGoogle Scholar
  71. 71.
    Shenoy S, Shekhar P, Heinrich F, Daou M-C, Gericke A, Ross AH, Lösche M (2012) Membrane association of the PTEN tumor suppressor: molecular details of the protein-membrane complex from SPR binding studies and neutron reflection. PLoS One 7:e32591PubMedGoogle Scholar
  72. 72.
    Singh G, Odriozola L, Guan H, Kennedy CR, Chan AM (2011) Characterization of a novel PTEN mutation in MDA-MB-453 breast carcinoma cell line. BMC Cancer 11:490PubMedGoogle Scholar
  73. 73.
    van den Berg B, Tessari M, Boelens R, Dijkman R, de Haas GH, Kaptein R, Verheij HM (1995) NMR structures of phospholipase A2 reveal conformational changes during interfacial activation. Nat Struct Biol 2:402–406PubMedGoogle Scholar
  74. 74.
    Boegeman SC, Deems RA, Dennis EA (2004) Phospholipid binding and the activation of group IA secreted phospholipase A2. Biochemistry 43:3907–3916PubMedGoogle Scholar
  75. 75.
    Bahnson BJ (2005) Structure, function and interfacial allosterism in phospholipase A2: insight from the anion-assisted dimer. Arch Biochem Biophys 433:96–106PubMedGoogle Scholar
  76. 76.
    Wishart MJ, Dixon JE (2002) PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. Trends Cell Biol 12:579–585PubMedGoogle Scholar
  77. 77.
    Iijima M, Devreotes PN (2002) Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Cell 109:599–610PubMedGoogle Scholar
  78. 78.
    Yeung T, Heit B, Dubuisson J-F, Fairn GD, Chiu B, Inman R, Kapus A, Swanson M, Grinstein S (2009) Contribution of phosphatidylserine to membrane surface charge and protein targeting during phagosome maturation. J Cell Biol 185:917–928PubMedGoogle Scholar
  79. 79.
    Kooijman EE, King KE, Gangoda M, Gericke A (2009) Ionization properties of phosphatidylinositol polyphosphates in mixed model membranes. Biochemistry 48:9360–9371PubMedGoogle Scholar
  80. 80.
    Redfern RE, Daou M, Li L, Munson M, Gericke A, Ross AH (2010) A mutant form of PTEN linked to autism. Protein Sci 19:1948–1956PubMedGoogle Scholar
  81. 81.
    Cai H, Devreotes PN (2011) Moving in the right direction: how eukaryotic cells migrate along chemical gradients. Semin Cell Dev Biol 22:834–841PubMedGoogle Scholar
  82. 82.
    Wang Y, Chen C-L, Iijima M (2011) Signaling mechanisms for chemotaxis. Dev Growth Differ 53:495–502PubMedGoogle Scholar
  83. 83.
    Willard SS, Devreotes PN (2006) Signaling pathways mediating chemotaxis in the social amoeba, Dictyostelium discoideum. Eur J Cell Biol 85:897–904PubMedGoogle Scholar
  84. 84.
    Franca-Koh J, Kamimura Y, Devreotes PN (2007) Leading-edge research: PtdIns(3,4,5)P3 and directed migration. Nat Cell Biol 9:15–17PubMedGoogle Scholar
  85. 85.
    Weiner OD (2002) Regulation of cell polarity during eukaryotic chemotaxis: the chemotactic compass. Curr Opin Cell Biol 14:196–202PubMedGoogle Scholar
  86. 86.
    Nishio M, Watanabe K-i, Sasaki J, Taya C, Takasuga S, Iizuka R, Balla T, Yamazaki M, Watanabe H, Itoh R, Kuroda S, Horie Y, Förster I, Mak TW, Yonekawa H, Penninger JM, Kanaho Y, Suzuki A, Sasaki T (2007) Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1. Nat Cell Biol 9:36–44PubMedGoogle Scholar
  87. 87.
    Rabinovsky R, Pochanard P, McNear C, Brachmann SM, Duke-Cohan JS, Garraway LA, Sellers WR (2009) p85 associates with unphosphorylated PTEN and the PTEN-associated complex. Mol Cell Biol 29:5377–5388PubMedGoogle Scholar
  88. 88.
    Tibarewal P, Zilidis G, Spinelli L, Schurch N, Maccario H, Gray A, Perera NM, Davidson L, Barton GJ, Leslie NR (2012) PTEN protein phosphatase activity correlates with control of gene expression and invasion, a tumor-suppressing phenotype, but not with AKT activity. Sci Signal 5:ra18PubMedGoogle Scholar
  89. 89.
    Villalba-Galea CA (2012) New insights in the activity of voltage sensitive phosphatases. Cell Signal 24:1541–1547PubMedGoogle Scholar
  90. 90.
    Murata Y, Iwasaki H, Sasaki M, Inaba K, Okamura Y (2005) Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor. Nature 435:1239–1243PubMedGoogle Scholar
  91. 91.
    Lacroix J, Halaszovich CR, Schreiber DN, Leitner MG, Bezanilla F, Oliver D, Villalba-Galea CA (2011) Controlling the activity of a phosphatase and tensin homolog (PTEN) by membrane potential. J Biol Chem 286:17945–17953PubMedGoogle Scholar
  92. 92.
    Hobiger K, Utesch T, Mroginski MA, Friedrich T (2012) Coupling of Ci-VSP modules requires a combination of structure and electrostatics within the linker. Biophys J 102:1313–1322PubMedGoogle Scholar
  93. 93.
    Kohout SC, Bell SC, Liu L, Xu Q, Minor DL, Isacoff EY (2010) Electrochemical coupling in the voltage-dependent phosphatase Ci-VSP. Nat Chem Biol 6:369–375PubMedGoogle Scholar
  94. 94.
    Matsuda M, Takeshita K, Kurokawa T, Sakata S, Suzuki M, Yamashita E, Okamura Y, Nakagawa A (2011) Crystal structure of the cytoplasmic phosphatase and tensin homolog (PTEN)-like region of Ciona intestinalis voltage-sensing phosphatase provides insight into substrate specificity and redox regulation of the phosphoinositide phosphatase activity. J Biol Chem 286:23368–23377PubMedGoogle Scholar
  95. 95.
    Liu L, Kohout SC, Xu Q, Müller S, Kimberlin CR, Isacoff EY, Minor DL (2012) A glutamate switch controls voltage-sensitive phosphatase function. Nat Struct Mol Biol 19:633–641PubMedGoogle Scholar
  96. 96.
    Schalke M, Lösche M (2000) Structural models of lipid surface monolayers from x-ray and neutron reflectivity measurements. Adv Colloid Interface Sci 88:243–274PubMedGoogle Scholar
  97. 97.
    Shenoy SS, Nanda H, Lösche M (2012) Membrane association of the PTEN tumor suppressor: electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail. J Struct Biol 180:394–408Google Scholar
  98. 98.
    Huang J, Yan J, Zhang J, Zhu S, Wang Y, Shi T, Zhu C, Chen C, Liu X, Cheng J, Mustelin T, Feng G-S, Chen G, Yu J (2012) SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane. Nat Commun 3:911–922PubMedGoogle Scholar
  99. 99.
    Liu F, Wagner S, Campbell RB, Nickerson JA, Schiffer CA, Ross AH (2005) PTEN enters the nucleus by diffusion. J Cell Biochem 96:221–234PubMedGoogle Scholar
  100. 100.
    Cornell BA, Braach-Maksvytis VLB, King LB, Osman PDJ, Raguse B, Wieczorek L, Pace RJ (1997) A biosensor that uses ion-channel switches. Nature 387:580–583PubMedGoogle Scholar
  101. 101.
    Tanaka M, Sackmann E (2005) Polymer-supported membranes as models of the cell surface. Nature 437:656–663PubMedGoogle Scholar
  102. 102.
    Tamm LK, McConnell HM (1985) Supported phospholipid bilayers. Biophys J 47:105–113PubMedGoogle Scholar
  103. 103.
    Sackmann E (1996) Supported membranes: scientific and practical applications. Science 271:43–48PubMedGoogle Scholar
  104. 104.
    Crane JM, Tamm LK (2004) Role of cholesterol in the formation and nature of lipid rafts in planar and spherical model membranes. Biophys J 86:2965–2979PubMedGoogle Scholar
  105. 105.
    Knoll W, Naumann R, Friedrich M, Robertson JWF, Lösche M, Heinrich F, McGillivray DJ, Schuster B, Gufler PC, Pum D, Sleytr UB (2008) Solid supported functional lipid membranes based on monomolecular protein sheet crystals: new concepts for the biomimetic functionalization of solid surfaces. Biointerphases 3:FA125–FA135PubMedGoogle Scholar
  106. 106.
    Smith HL, Jablin MS, Vidyasagar A, Saiz J, Watkins E, Toomey R, Hurd AJ, Majewski J (2009) Model lipid membranes on a tunable polymer cushion. Phys Rev Lett 102:228102PubMedGoogle Scholar
  107. 107.
    Jeuken LJC, Connell SD, Henderson PJF, Gennis RB, Evans SD, Bushby RJ (2006) Redox enzymes in tethered membranes. J Am Chem Soc 128:1711–1716PubMedGoogle Scholar
  108. 108.
    Vockenroth IK, Ohm C, Robertson JWF, McGillivray DJ, Lösche M, Köper I (2008) Stable insulating tethered bilayer membranes. Biointerphases 3:FA68–FA73PubMedGoogle Scholar
  109. 109.
    Sackmann E, Tanaka M (2000) Supported membranes on soft polymer cushions: fabrication, characterization and applications. Trends Biotechnol 18:58–64PubMedGoogle Scholar
  110. 110.
    Kiessling V, Tamm LK (2003) Measuring distances in supported bilayers by fluorescence interference-contrast microscopy: polymer supports and SNARE proteins. Biophys J 84:408–418PubMedGoogle Scholar
  111. 111.
    Garg S, Rühe J, Lüdtke K, Jordan R, Naumann CA (2007) Domain registration in raft-mimicking lipid mixtures studied using polymer-tethered lipid bilayers. Biophys J 92:1263–1270PubMedGoogle Scholar
  112. 112.
    Lin J, Szymanski J, Searson PC, Hristova K (2010) Effect of a polymer cushion on the electrical properties and stability of surface-supported lipid bilayers. Langmuir 26:3544–3548PubMedGoogle Scholar
  113. 113.
    Purrucker O, Förtig A, Jordan R, Tanaka M (2004) Supported membranes with well-defined polymer tethers-incorporation of cell receptors. ChemPhysChem 5:327–335PubMedGoogle Scholar
  114. 114.
    McGillivray DJ, Valincius G, Vanderah DJ, Febo-Ayala W, Woodward JT, Heinrich F, Kasianowicz JJ, Lösche M (2007) Molecular-scale structural and functional characterization of sparsely tethered bilayer lipid membranes. Biointerphases 2:21–33PubMedGoogle Scholar
  115. 115.
    Heinrich F, Ng T, Vanderah DJ, Shekhar P, Mihailescu M, Nanda H, Lösche M (2009) A new lipid anchor for sparsely tethered bilayer lipid membranes. Langmuir 25:4219–4229PubMedGoogle Scholar
  116. 116.
    McGillivray DJ, Valincius G, Heinrich F, Robertson JWF, Vanderah DJ, Febo-Ayala W, Ignatjev I, Lösche M, Kasianowicz JJ (2009) Structure of functional Staphylococcus aureus α-hemolysin channels in tethered bilayer lipid membranes. Biophys J 96:1547–1553PubMedGoogle Scholar
  117. 117.
    Robelek R, Lemker ES, Wiltschi B, Kirste V, Naumann R, Oesterhelt D, Sinner EK (2007) Incorporation of in vitro synthesized GPCR into a tethered artificial lipid membrane system. Angew Chem Int Ed Engl 46:605–608PubMedGoogle Scholar
  118. 118.
    Sumino A, Dewa T, Takeuchi T, Sugiura R, Sasaki N, Misawa N, Tero R, Urisu T, Gardiner AT, Cogdell RJ, Hashimoto H, Nango M (2011) Construction and structural analysis of tethered lipid bilayer containing photosynthetic antenna proteins for functional analysis. Biomacromolecules 12:2850–2858PubMedGoogle Scholar
  119. 119.
    Nanda H, Datta SAK, Heinrich F, Lösche M, Rein A, Krueger S, Curtis JE (2010) Electrostatic interactions and binding orientation of HIV-1 matrix, studied by neutron reflectivity. Biophys J 99:2516–2524PubMedGoogle Scholar
  120. 120.
    Valincius G, Heinrich F, Budvytyte R, Vanderah DJ, McGillivray DJ, Sokolov Y, Hall JE, Lösche M (2008) Soluble amyloid β-oligomers affect dielectric membrane properties by bilayer insertion and domain formation: implications for cell toxicity. Biophys J 95:4845–4861PubMedGoogle Scholar
  121. 121.
    Valincius G, Meskauskas T, Ivanauskas F (2012) Electrochemical impedance spectroscopy of tethered bilayer membranes. Langmuir 28:977–990PubMedGoogle Scholar
  122. 122.
    Valincius G, McGillivray DJ, Febo-Ayala W, Vanderah DJ, Kasianowicz JJ, Lösche M (2006) Enzyme activity to augment the characterization of tethered bilayer membranes. J Phys Chem B 110:10213–10216PubMedGoogle Scholar
  123. 123.
    Wiltschi B, Knoll W, Sinner E-K (2006) Binding assays with artificial tethered membranes using surface plasmon resonance. Methods 39:134–146PubMedGoogle Scholar
  124. 124.
    Shekhar P, Nanda H, Lösche M, Heinrich F (2011) Continuous distribution model for the investigation of complex molecular architectures near interfaces with scattering techniques. J Appl Phys 110:102216-102211–102216-102212Google Scholar
  125. 125.
    Datta SAK, Heinrich F, Raghunandan S, Krueger S, Curtis JE, Rein A, Nanda H (2011) HIV-1 Gag extension: conformational changes require simultaneous interaction with membrane and nucleic acid. J Mol Biol 406:205–214PubMedGoogle Scholar
  126. 126.
    Curtis JE, Raghunandran S, Nanda H, Krueger S (2012) SASSIE: a program to study intrinsically disordered biological molecules and macromolecular ensembles using experimental scattering constraints. Comp Phys Commun 183:382–389Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Arne Gericke
    • 1
  • Nicholas R. Leslie
    • 2
  • Mathias Lösche
    • 3
    • 4
    • 5
  • Alonzo H. Ross
    • 6
    • 7
    Email author
  1. 1.Department of Chemistry and BiochemistryWorcester Polytechnic InstituteWorcesterUSA
  2. 2.Division of Molecular PhysiologyUniversity of DundeeDundeeUK
  3. 3.Department of PhysicsCarnegie Mellon UniversityPittsburghUSA
  4. 4.Department of Biomedical EngineeringCarnegie Mellon UniversityPittsburghUSA
  5. 5.The National Institute of Standards and TechnologyCenter for Neutron ResearchGaithersburgUSA
  6. 6.Department of BiochemistryUniversity of Massachusetts Medical SchoolWorcesterUSA
  7. 7.Department of Molecular PharmacologyUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations