Skip to main content

Advertisement

Springer Nature Link
Log in

The multifaceted role of PIP2 in leukocyte biology

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP2) represents about 1 % of plasma membrane phospholipids and behaves as a pleiotropic regulator of a striking number of fundamental cellular processes. In recent years, an increasing body of literature has highlighted an essential role of PIP2 in multiple aspects of leukocyte biology. In this emerging picture, PIP2 is envisaged as a signalling intermediate itself and as a membrane-bound regulator and a scaffold of proteins with specific PIP2 binding domains. Indeed PIP2 plays a key role in several functions. These include directional migration in neutrophils, integrin-dependent adhesion in T lymphocytes, phagocytosis in macrophages, lysosomes secretion and trafficking at immune synapse in cytolytic effectors and secretory cells, calcium signals and gene transcription in B lymphocytes, natural killer cells and mast cells. The coordination of these different aspects relies on the spatio-temporal organisation of distinct PIP2 pools, generated by the main PIP2 generating enzyme, phosphatidylinositol 4-phosphate 5-kinase (PIP5K). Three different isoforms of PIP5K, named α, β and γ, and different splice variants have been described in leukocyte populations. The isoform-specific coupling of specific isoforms of PIP5K to different families of activating receptors, including integrins, Fc receptors, toll-like receptors and chemokine receptors, is starting to be reported. Furthermore, PIP2 is turned over by multiple metabolising enzymes including phospholipase C (PLC) γ and phosphatidylinositol 3-kinase (PI3K) which, along with Rho family small G proteins, is widely involved in strategic functions within the immune system. The interplay between PIP2, lipid-modifying enzymes and small G protein-regulated signals is also discussed.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kwiatkowska K (2010) One lipid, multiple functions: how various pools of PI(4,5)P(2) are created in the plasma membrane. Cell Mol Life Sci 67:3927–3946

    Article  CAS  PubMed  Google Scholar 

  2. Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657

    Article  PubMed  CAS  Google Scholar 

  3. van den Bout I, Divecha N (2009) PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions. J Cell Sci 122:3837–3850

    Article  PubMed  CAS  Google Scholar 

  4. Ishihara H, Shibasaki Y, Kizuki N, Katagiri H, Yazaki Y, Asano T, Oka Y (1996) Cloning of cDNAs encoding two isoforms of 68-kDa type I phosphatidylinositol-4-phosphate 5-kinase. J Biol Chem 271:23611–23614

    Article  CAS  PubMed  Google Scholar 

  5. Ishihara H, Shibasaki Y, Kizuki N, Wada T, Yazaki Y, Asano T, Oka Y (1998) Type I phosphatidylinositol-4-phosphate 5-kinases. Cloning of the third isoform and deletion/substitution analysis of members of this novel lipid kinase family. J Biol Chem 273:8741–8748

    Article  CAS  PubMed  Google Scholar 

  6. Loijens JC, Anderson RA (1996) Type I phosphatidylinositol-4-phosphate 5-kinases are distinct members of this novel lipid kinase family. J Biol Chem 271:32937–32943

    Article  CAS  PubMed  Google Scholar 

  7. Chatah NE, Abrams CS (2001) G-protein-coupled receptor activation induces the membrane translocation and activation of phosphatidylinositol-4-phosphate 5-kinase I alpha by a Rac- and Rho-dependent pathway. J Biol Chem 276:34059–34065

    Article  CAS  PubMed  Google Scholar 

  8. Doughman RL, Firestone AJ, Wojtasiak ML, Bunce MW, Anderson RA (2003) Membrane ruffling requires coordination between type Ialpha phosphatidylinositol phosphate kinase and Rac signaling. J Biol Chem 278:23036–23045

    Article  CAS  PubMed  Google Scholar 

  9. Barbieri MA, Heath CM, Peters EM, Wells A, Davis JN, Stahl PD (2001) Phosphatidylinositol-4-phosphate 5-kinase-1beta is essential for epidermal growth factor receptor-mediated endocytosis. J Biol Chem 276:47212–47216

    Article  CAS  PubMed  Google Scholar 

  10. Coppolino MG, Krause M, Hagendorff P, Monner DA, Trimble W, Grinstein S, Wehland J, Sechi AS (2001) Evidence for a molecular complex consisting of Fyb/SLAP, SLP-76, Nck, VASP and WASP that links the actin cytoskeleton to Fc{gamma} receptor signalling during phagocytosis. J Cell Sci 114:4307–4318

    CAS  PubMed  Google Scholar 

  11. Giudici ML, Lee K, Lim R, Irvine RF (2006) The intracellular localisation and mobility of Type Igamma phosphatidylinositol 4P 5-kinase splice variants. FEBS Lett 580:6933–6937

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Ling K, Doughman RL, Firestone AJ, Bunce MW, Anderson RA (2002) Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 420:89–93

    Article  CAS  PubMed  Google Scholar 

  13. Choi S, Thapa N, Tan X, Hedman AC, Anderson RA (2015) PIP kinases define PI4,5P2 signaling specificity by association with effectors. Biochim Biophys Acta 1851:711–723

    Article  CAS  PubMed  Google Scholar 

  14. McLaughlin S, Murray D (2005) Plasma membrane phosphoinositide organization by protein electrostatics. Nature 438:605–611

    Article  CAS  PubMed  Google Scholar 

  15. Hall A (2012) Rho family GTPases. Biochem Soc Trans 40:1378–1382

    Article  CAS  PubMed  Google Scholar 

  16. Chong LD, Traynor-Kaplan A, Bokoch GM, Schwartz MA (1994) The small GTP-binding protein Rho regulates a phosphatidylinositol 4-phosphate 5-kinase in mammalian cells. Cell 79:507–513

    Article  CAS  PubMed  Google Scholar 

  17. Ren XD, Bokoch GM, Traynor-Kaplan A, Jenkins GH, Anderson RA, Schwartz MA (1996) Physical association of the small GTPase Rho with a 68-kDa phosphatidylinositol 4-phosphate 5-kinase in Swiss 3T3 cells. Mol Biol Cell 7:435–442

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Weernink PA, Meletiadis K, Hommeltenberg S, Hinz M, Ishihara H, Schmidt M, Jakobs KH (2004) Activation of type I phosphatidylinositol 4-phosphate 5-kinase isoforms by the Rho GTPases, RhoA, Rac1, and Cdc42. J Biol Chem 279:7840–7849

    Article  CAS  PubMed  Google Scholar 

  19. Oude Weernink PA, Schulte P, Guo Y, Wetzel J, Amano M, Kaibuchi K, Haverland S, Voss M, Schmidt M, Mayr GW, Jakobs KH (2000) Stimulation of phosphatidylinositol-4-phosphate 5-kinase by Rho-kinase. J Biol Chem 275:10168–10174

    Article  CAS  PubMed  Google Scholar 

  20. Coppolino MG, Dierckman R, Loijens J, Collins RF, Pouladi M, Jongstra-Bilen J, Schreiber AD, Trimble WS, Anderson R, Grinstein S (2002) Inhibition of phosphatidylinositol-4-phosphate 5-kinase Ialpha impairs localized actin remodeling and suppresses phagocytosis. J Biol Chem 277:43849–43857

    Article  CAS  PubMed  Google Scholar 

  21. Tolias KF, Hartwig JH, Ishihara H, Shibasaki Y, Cantley LC, Carpenter CL (2000) Type Ialpha phosphatidylinositol-4-phosphate 5-kinase mediates Rac-dependent actin assembly. Curr Biol 10:153–156

    Article  CAS  PubMed  Google Scholar 

  22. Funakoshi Y, Hasegawa H, Kanaho Y (2011) Regulation of PIP5K activity by Arf6 and its physiological significance. J Cell Physiol 226:888–895

    Article  CAS  PubMed  Google Scholar 

  23. Myers KR, Casanova JE (2008) Regulation of actin cytoskeleton dynamics by Arf-family GTPases. Trends Cell Biol 18:184–192

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Honda A, Nogami M, Yokozeki T, Yamazaki M, Nakamura H, Watanabe H, Kawamoto K, Nakayama K, Morris AJ, Frohman MA, Kanaho Y (1999) Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle formation. Cell 99:521–532

    Article  CAS  PubMed  Google Scholar 

  25. Krauss M, Kinuta M, Wenk MR, De Camilli P, Takei K, Haucke V (2003) ARF6 stimulates clathrin/AP-2 recruitment to synaptic membranes by activating phosphatidylinositol phosphate kinase type Igamma. J Cell Biol 162:113–124

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Perez-Mansilla B, Ha VL, Justin N, Wilkins AJ, Carpenter CL, Thomas GM (2006) The differential regulation of phosphatidylinositol 4-phosphate 5-kinases and phospholipase D1 by ADP-ribosylation factors 1 and 6. Biochim Biophys Acta 1761:1429–1442

    Article  CAS  PubMed  Google Scholar 

  27. Jenkins GH, Fisette PL, Anderson RA (1994) Type I phosphatidylinositol 4-phosphate 5-kinase isoforms are specifically stimulated by phosphatidic acid. J Biol Chem 269:11547–11554

    CAS  PubMed  Google Scholar 

  28. Moritz A, De Graan PN, Gispen WH, Wirtz KW (1992) Phosphatidic acid is a specific activator of phosphatidylinositol-4-phosphate kinase. J Biol Chem 267:7207–7210

    CAS  PubMed  Google Scholar 

  29. Divecha N, Roefs M, Halstead JR, D’Andrea S, Fernandez-Borga M, Oomen L, Saqib KM, Wakelam MJ, D’Santos C (2000) Interaction of the type Ialpha PIPkinase with phospholipase D: a role for the local generation of phosphatidylinositol 4, 5-bisphosphate in the regulation of PLD2 activity. EMBO J 19:5440–5449

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Powner DJ, Payne RM, Pettitt TR, Giudici ML, Irvine RF, Wakelam MJ (2005) Phospholipase D2 stimulates integrin-mediated adhesion via phosphatidylinositol 4-phosphate 5-kinase Igamma b. J Cell Sci 118:2975–2986

    Article  CAS  PubMed  Google Scholar 

  31. Exton JH (2002) Regulation of phospholipase D. FEBS Lett 531:58–61

    Article  CAS  PubMed  Google Scholar 

  32. Itoh T, Ishihara H, Shibasaki Y, Oka Y, Takenawa T (2000) Autophosphorylation of type I phosphatidylinositol phosphate kinase regulates its lipid kinase activity. J Biol Chem 275:19389–19394

    Article  CAS  PubMed  Google Scholar 

  33. Park SJ, Itoh T, Takenawa T (2001) Phosphatidylinositol 4-phosphate 5-kinase type I is regulated through phosphorylation response by extracellular stimuli. J Biol Chem 276:4781–4787

    Article  CAS  PubMed  Google Scholar 

  34. Aikawa Y, Martin TF (2003) ARF6 regulates a plasma membrane pool of phosphatidylinositol(4,5)bisphosphate required for regulated exocytosis. J Cell Biol 162:647–659

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Lee SY, Voronov S, Letinic K, Nairn AC, Di Paolo G, De Camilli P (2005) Regulation of the interaction between PIPKI gamma and talin by proline-directed protein kinases. J Cell Biol 168:789–799

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Ling K, Doughman RL, Iyer VV, Firestone AJ, Bairstow SF, Mosher DF, Schaller MD, Anderson RA (2003) Tyrosine phosphorylation of type Igamma phosphatidylinositol phosphate kinase by Src regulates an integrin-talin switch. J Cell Biol 163:1339–1349

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Halstead JR, van Rheenen J, Snel MH, Meeuws S, Mohammed S, D’Santos CS, Heck AJ, Jalink K, Divecha N (2006) A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis. Curr Biol 16:1850–1856

    Article  CAS  PubMed  Google Scholar 

  38. Blank U, Rivera J (2004) The ins and outs of IgE-dependent mast-cell exocytosis. Trends Immunol 25:266–273

    Article  CAS  PubMed  Google Scholar 

  39. Hoth M, Penner R (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–356

    Article  CAS  PubMed  Google Scholar 

  40. Vig M, Kinet JP (2007) The long and arduous road to CRAC. Cell Calcium 42:157–162

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T (2005) STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol 15:1235–1241

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Veliçelebi G, Stauderman KA (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169:435–445

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–185

    Article  CAS  PubMed  Google Scholar 

  44. Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP (2006) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220–1223

    Article  CAS  PubMed  Google Scholar 

  45. Way G, O’luanaigh N, Cockcroft S (2000) Activation of exocytosis by cross-linking of the IgE receptor is dependent on ADP-ribosylation factor 1-regulated phospholipase D in RBL-2H3 mast cells: evidence that the mechanism of activation is via regulation of phosphatidylinositol 4,5-bisphosphate synthesis. Biochem J 346(Pt 1):63–70

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Hammond GR, Dove SK, Nicol A, Pinxteren JA, Zicha D, Schiavo G (2006) Elimination of plasma membrane phosphatidylinositol (4,5)-bisphosphate is required for exocytosis from mast cells. J Cell Sci 119(Pt 10):2084–2094

    Article  CAS  PubMed  Google Scholar 

  47. Vasudevan L, Jeromin A, Volpicelli-Daley L, De Camilli P, Holowka D, Baird B (2009) The beta- and gamma-isoforms of type I PIP5K regulate distinct stages of Ca2+ signaling in mast cells. J Cell Sci 122(Pt 14):2567–2574

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Calloway N, Owens T, Corwith K, Rodgers W, Holowka D, Baird B (2011) Stimulated association of STIM1 and Orai1 is regulated by the balance of PtdIns(4,5)P2 between distinct membrane pools. J Cell Sci 124(Pt 15):2602–2610

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Higgs HN, Pollard TD (2000) Activation by Cdc42 and PIP(2) of Wiskott–Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex. J Cell Biol 150:1311–1320

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Welch MD, Mullins RD (2002) Cellular control of actin nucleation. Annu Rev Cell Dev Biol 18:247–288

    Article  CAS  PubMed  Google Scholar 

  51. Papayannopoulos V, Co C, Prehoda KE, Snapper S, Taunton J, Lim WA (2005) A polybasic motif allows N-WASP to act as a sensor of PIP(2) density. Mol Cell 17:181–191

    Article  CAS  PubMed  Google Scholar 

  52. Rivera GM, Vasilescu D, Papayannopoulos V, Lim WA, Mayer BJ (2009) A reciprocal interdependence between Nck and PI(4,5)P(2) promotes localized N-WASp-mediated actin polymerization in living cells. Mol Cell 36:525–535

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Wollman R, Meyer T (2012) Coordinated oscillations in cortical actin and Ca2+ correlate with cycles of vesicle secretion. Nat Cell Biol 14:1261–1269

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Sasaki J, Sasaki T, Yamazaki M, Matsuoka K, Taya C, Shitara H, Takasuga S, Nishio M, Mizuno K, Wada T et al (2005) Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I {alpha}. J Exp Med 201:859–870

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Rougerie P, Miskolci V, Cox D (2013) Generation of membrane structures during phagocytosis and chemotaxis of macrophages: role and regulation of the actin cytoskeleton. Immunol Rev 256:222–239

    Article  CAS  PubMed  Google Scholar 

  56. Botelho RJ, Teruel M, Dierckman R, Anderson R, Wells A, York JD, Meyer T, Grinstein S (2000) Localized biphasic changes in phosphatidylinositol-4,5-bisphosphate at sites of phagocytosis. J Cell Biol 151:1353–1368

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Scott CC, Dobson W, Botelho RJ, Coady-Osberg N, Chavrier P, Knecht DA, Heath C, Stahl P, Grinstein S (2005) Phosphatidylinositol-4,5-bisphosphate hydrolysis directs actin remodeling during phagocytosis. J Cell Biol 169:139–149

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Szymanska E, Sobota A, Czurylo E, Kwiatkowska K (2008) Expression of PI(4,5)P2-binding proteins lowers the PI(4,5)P2level and inhibits FcgammaRIIA-mediated cell spreading and phagocytosis. Eur J Immunol 38:260–272

    Article  CAS  PubMed  Google Scholar 

  59. Mao YS, Yamaga M, Zhu X, Wei Y, Sun HQ, Wang J, Yun M, Wang Y, Di Paolo G, Bennett M et al (2009) Essential and unique roles of PIP5K-gamma and -alpha in Fcgamma receptor-mediated phagocytosis. J Cell Biol 184:281–296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Uchida H, Kondo A, Yoshimura Y, Mazaki Y, Sabe H (2001) PAG3/Papalpha/KIAA0400, a GTPase-activating protein for ADP-ribosylation factor (ARF), regulates ARF6 in Fcgamma receptor-mediated phagocytosis of macrophages. J Exp Med 193:955–966

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Zhang Q, Cox D, Tseng CC, Donaldson JG, Greenberg S (1998) A requirement for ARF6 in Fcgamma receptor-mediated phagocytosis in macrophages. J Biol Chem 273:19977–19981

    Article  CAS  PubMed  Google Scholar 

  62. Niedergang F, Colucci-Guyon E, Dubois T, Raposo G, Chavrier P (2003) ADP ribosylation factor 6 is activated and controls membrane delivery during phagocytosis in macrophages. J Cell Biol 161:1143–1150

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    Article  CAS  PubMed  Google Scholar 

  64. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995

    Article  CAS  PubMed  Google Scholar 

  65. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511

    Article  CAS  PubMed  Google Scholar 

  66. Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T et al (2002) Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324–329

    Article  CAS  PubMed  Google Scholar 

  67. Kagan JC, Medzhitov R (2006) Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125:943–955

    Article  CAS  PubMed  Google Scholar 

  68. Lee SY, Kim B, Jeong HK, Min KJ, Liu T, Park JY, Joe EH, Jou I (2010) Enhanced phosphatidylinositol 4-phosphate 5-kinase alpha expression and PI(4,5)P2 production in LPS-stimulated microglia. Neurochem Int 57:600–607

    Article  CAS  PubMed  Google Scholar 

  69. Nguyen TT, Kim YM, Kim TD, Le OT, Kim JJ, Kang HC, Hasegawa H, Kanaho Y, Jou I, Lee SY (2013) Phosphatidylinositol 4-phosphate 5-kinase alpha facilitates Toll-like receptor 4-mediated microglial inflammation through regulation of the Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) location. J Biol Chem 288:5645–5659

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Luo BH, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Rose DM, Alon R, Ginsberg MH (2007) Integrin modulation and signaling in leukocyte adhesion and migration. Immunol Rev 218:126–134

    Article  CAS  PubMed  Google Scholar 

  72. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR (2003) Cell migration: integrating signals from front to back. Science 302:1704–1709

    Article  CAS  PubMed  Google Scholar 

  73. Mañes S, Gómez-Moutón C, Lacalle RA, Jiménez-Baranda S, Mira E, Martínez AC (2005) Mastering time and space: immune cell polarization and chemotaxis. Semin Immunol 17:77–86

    Article  PubMed  CAS  Google Scholar 

  74. Sharma VP, DesMarais V, Sumners C, Shaw G, Narang A (2008) Immunostaining evidence for PI(4,5)P2 localization at the leading edge of chemoattractant-stimulated HL-60 cells. J Leukoc Biol 84:440–447

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Xu W, Wang P, Petri B, Zhang Y, Tang W, Sun L, Kress H, Mann T, Shi Y, Kubes P, Wu D (2010) Integrin-induced PIP5K1C kinase polarization regulates neutrophil polarization, directionality, and in vivo infiltration. Immunity 33:340–350

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Lokuta MA, Senetar MA, Bennin DA, Nuzzi PA, Chan KT, Ott VL, Huttenlocher A (2007) Type Igamma PIP kinase is a novel uropod component that regulates rear retraction during neutrophil chemotaxis. Mol Biol Cell 18:5069–5080

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Lacalle RA, Peregil RM, Albar JP, Merino E, Martínez-AC Mérida I, Mañes S (2007) Type I phosphatidylinositol 4-phosphate 5-kinase controls neutrophil polarity and directional movement. J Cell Biol 179:1539–1553

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Niggli V (2005) Regulation of protein activities by phosphoinositide phosphates. Annu Rev Cell Dev Biol 21:57–79

    Article  CAS  PubMed  Google Scholar 

  79. Takahashi K, Sasaki T, Mammoto A, Takaishi K, Kameyama T, Tsukita S, Takai Y (1997) Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J Biol Chem 272:23371–23375

    Article  CAS  PubMed  Google Scholar 

  80. Zhang N, Bevan MJ (2011) CD8+ T cells: foot soldiers of the immune system. Immunity 35:161–168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9:495–502

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Orange JS (2008) Formation and function of the lytic NK-cell immunological synapse. Nat Rev Immunol 8:713–725

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Galandrini R, Capuano C, Santoni A (2013) Activation of lymphocyte cytolytic machinery: where are we? Front Immunol 4:390. doi:10.3389/fimmu.2013.00390

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  85. Kerr WG, Colucci F (2011) Inositol phospholipid signaling and the biology of natural killer cells. J Innate Immun 3:249–257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Micucci F, Capuano C, Marchetti E, Piccoli M, Frati L, Santoni A, Galandrini R (2008) PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway. Blood 111:4165–4172

    Article  CAS  PubMed  Google Scholar 

  87. Galandrini R, Micucci F, Tassi I, Cifone MG, Cinque B, Piccoli M, Frati L, Santoni A (2005) Arf6: a new player in FcgammaRIIIA lymphocyte-mediated cytotoxicity. Blood 106:577–583

    Article  CAS  PubMed  Google Scholar 

  88. Stinchcombe JC, Bossi G, Booth S, Griffiths GM (2001) The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15:751–761

    Article  CAS  PubMed  Google Scholar 

  89. Orange JS, Harris KE, Andzelm MM, Valter MM, Geha RS, Strominger JL (2003) The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proc Natl Acad Sci USA 100:14151–14156

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Stabile H, Carlino C, Mazza C, Giliani S, Morrone S, Notarangelo LD, Notarangelo LD, Santoni A, Gismondi A (2010) Impaired NK-cell migration in WAS/XLT patients: role of Cdc42/WASp pathway in the control of chemokine-induced beta2 integrin high-affinity state. Blood 115:2818–2826

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Orange JS, Ramesh N, Remold-O’Donnell E, Sasahara Y, Koopman L, Byrne M, Bonilla FA, Rosen FS, Geha RS, Strominger JL (2002) Wiskott–Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci USA 99:11351–11356

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Gismondi A, Cifaldi L, Mazza C, Giliani S, Parolini S, Morrone S, Jacobelli J, Bandiera E, Notarangelo L, Santoni A (2004) Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect. Blood 104:436–443

    Article  CAS  PubMed  Google Scholar 

  93. Butler B, Cooper JA (2009) Distinct roles for the actin nucleators Arp2/3 and hDia1 during NK-mediated cytotoxicity. Curr Biol 19:1886–1896

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. De Meester J, Calvez R, Valitutti S, Dupré L (2010) The Wiskott–Aldrich syndrome protein regulates CTL cytotoxicity and is required for efficient killing of B cell lymphoma targets. J Leukoc Biol 88:1031–1040

    Article  PubMed  CAS  Google Scholar 

  95. Mace EM, Zhang J, Siminovitch KA, Takei F (2010) Elucidation of the integrin LFA-1-mediated signaling pathway of actin polarization in natural killer cells. Blood 116:1272–1279

    Article  CAS  PubMed  Google Scholar 

  96. Anthis NJ, Wegener KL, Ye F, Kim C, Goult BT, Lowe ED, Vakonakis I, Bate N, Critchley DR, Ginsberg MH, Campbell ID (2009) The structure of an integrin/talin complex reveals the basis of inside-out signal transduction. EMBO J 28:3623–3632

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Pores-Fernando AT, Zweifach A (2009) Calcium influx and signaling in cytotoxic T-lymphocyte lytic granule exocytosis. Immunol Rev 231:160–173

    Article  CAS  PubMed  Google Scholar 

  98. Tassi I, Presti R, Kim S, Yokoyama WM, Gilfillan S, Colonna M (2005) Phospholipase C-gamma 2 is a critical signaling mediator for murine NK cell activating receptors. J Immunol 175:749–754

    Article  CAS  PubMed  Google Scholar 

  99. Maul-Pavicic A, Chiang SC, Rensing-Ehl A, Jessen B, Fauriat C, Wood SM, Sjöqvist S, Hufnagel M, Schulze I, Bass T et al (2011) ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis. Proc Natl Acad Sci USA 108:3324–3329

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Fowler KT, Andrews NW, Huleatt JW (2007) Expression and function of synaptotagmin VII in CTLs. J Immunol 178:1498–1504

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  101. Martin TF (2012) Role of PI(4,5)P(2) in vesicle exocytosis and membrane fusion. Subcell Biochem 59:111–130

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Bhat R, Watzl C (2007) Serial killing of tumor cells by human natural killer cells–enhancement by therapeutic antibodies. PLoS One 2(3):e326

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  103. Choi PJ, Mitchison TJ (2013) Imaging burst kinetics and spatial coordination during serial killing by single natural killer cells. Proc Natl Acad Sci USA 110:6488–6493

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Vanherberghen B, Olofsson PE, Forslund E, Sternberg-Simon M, Khorshidi MA, Pacouret S, Guldevall K, Enqvist M, Malmberg KJ, Mehr R, Önfelt B (2013) Classification of human natural killer cells based on migration behavior and cytotoxic response. Blood 121:1326–1334

    Article  CAS  PubMed  Google Scholar 

  105. Ménager MM, Ménasché G, Romao M, Knapnougel P, Ho CH, Garfa M, Raposo G, Feldmann J, Fischer A, de Saint Basile G (2007) Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nat Immunol 8:257–267

    Article  PubMed  CAS  Google Scholar 

  106. Liu D, Bryceson YT, Meckel T, Vasiliver-Shamis G, Dustin ML, Long EO (2009) Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses. Immunity 31:99–109

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Capuano C, Paolini R, Molfetta R, Frati L, Santoni A, Galandrini R (2012) PIP2-dependent regulation of Munc13-4 endocytic recycling: impact on the cytolytic secretory pathway. Blood 119:2252–2262

    Article  CAS  PubMed  Google Scholar 

  108. Posor Y, Eichhorn-Grünig M, Haucke V (2015) Phosphoinositides in endocytosis. Biochim Biophys Acta 1851:794–804

    Article  CAS  PubMed  Google Scholar 

  109. Bairstow SF, Ling K, Su X, Firestone AJ, Carbonara C, Anderson RA (2006) Type Igamma661 phosphatidylinositol phosphate kinase directly interacts with AP2 and regulates endocytosis. J Biol Chem 281:20632–20642

    Article  CAS  PubMed  Google Scholar 

  110. Di Paolo G, Moskowitz HS, Gipson K, Wenk MR, Voronov S, Obayashi M, Flavell R, Fitzsimonds RM, Ryan TA, De Camilli P (2004) Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking. Nature 431:415–422

    Article  PubMed  CAS  Google Scholar 

  111. Zheng J, Cahill SM, Lemmon MA, Fushman D, Schlessinger J, Cowburn D (1996) Identification of the binding site for acidic phospholipids on the pH domain of dynamin: implications for stimulation of GTPase activity. J Mol Biol 255:14–21

    Article  CAS  PubMed  Google Scholar 

  112. Arneson LN, Segovis CM, Gomez TS, Schoon RA, Dick CJ, Lou Z, Billadeau DD, Leibson PJ (2008) Dynamin 2 regulates granule exocytosis during NK cell-mediated cytotoxicity. J Immunol 181:6995–7001

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Davis DM, Dustin ML (2004) What is the importance of the immunological synapse? Trends Immunol 25:323–327

    Article  CAS  PubMed  Google Scholar 

  115. Li Y, Sedwick CE, Hu J, Altman A (2005) Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation. J Biol Chem 280:1217–1223

    Article  CAS  PubMed  Google Scholar 

  116. Wang D, Matsumoto R, You Y, Che T, Lin XY, Gaffen SL, Lin X (2004) CD3/CD28 costimulation-induced NF-kappaB activation is mediated by recruitment of protein kinase C-theta, Bcl10, and IkappaB kinase beta to the immunological synapse through CARMA1. Mol Cell Biol 24:164–171

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Gwack Y, Feske S, Srikanth S, Hogan PG, Rao A (2007) Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. Cell Calcium 42:145–156

    Article  CAS  PubMed  Google Scholar 

  118. Kane LP, Weiss A (2003) The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3. Immunol Rev 192:7–20

    Article  CAS  PubMed  Google Scholar 

  119. Fruman DA, Bismuth G (2009) Fine tuning the immune response with PI3K. Immunol Rev 228:253–272

    Article  CAS  PubMed  Google Scholar 

  120. August A, Sadra A, Dupont B, Hanafusa H (1997) Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase. Proc Natl Acad Sci USA 94:11227–11232

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Andjelkovic M, Maira SM, Cron P, Parker PJ, Hemmings BA (1999) Domain swapping used to investigate the mechanism of protein kinase B regulation by 3-phosphoinositide-dependent protein kinase 1 and Ser473 kinase. Mol Cell Biol 19:5061–5072

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Falasca M, Logan SK, Lehto VP, Baccante G, Lemmon MA, Schlessinger J (1998) Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting. EMBO J 17:414–422

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Viola A, Lanzavecchia A (1996) T cell activation determined by T cell receptor number and tunable thresholds. Science 273:104–106

    Article  CAS  PubMed  Google Scholar 

  124. Viola A, Schroeder S, Sakakibara Y, Lanzavecchia A (1999) T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 283:680–682

    Article  CAS  PubMed  Google Scholar 

  125. Tuosto L, Acuto O (1998) CD28 affects the earliest signaling events generated by TCR engagement. Eur J Immunol 28:2132–2142

    Article  Google Scholar 

  126. Acuto O, Michel F (2003) CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 3:939–951

    Article  CAS  PubMed  Google Scholar 

  127. Ward SG, Westwick J, Hall ND, Sansom DM (1993) Ligation of CD28 receptor by B7 induces formation of D-3 phosphoinositides in T lymphocytes independently of T cell receptor/CD3 activation. Eur J Immunol 23:2572–2577

    Article  CAS  PubMed  Google Scholar 

  128. Cai YC, Cefai D, Schneider H, Raab M, Nabavi N, Rudd CE (1995) Selective CD28pYMNM mutations implicate phosphatidylinositol 3-kinase in CD86-CD28-mediated costimulation. Immunity 3:417–426

    Article  CAS  PubMed  Google Scholar 

  129. Doughman RL, Firestone AJ, Anderson RA (2003) Phosphatidylinositol phosphate kinases put PI4,5P(2) in its place. J Membr Biol 194:77–89

    Article  CAS  PubMed  Google Scholar 

  130. Zaru R, Berrie CP, Iurisci C, Corda D, Valitutti S (2001) CD28 co-stimulates TCR/CD3-induced phosphoinositide turnover in human T lymphocytes. Eur J Immunol 31:2438–2447

    Article  CAS  PubMed  Google Scholar 

  131. Singleton KL, Roybal KT, Sun Y, Fu G, Gascoigne NR, van Oers NS, Wulfing C (2009) Spatiotemporal patterning during T cell activation is highly diverse. Sci Signal 2:ra15

    Article  PubMed Central  PubMed  Google Scholar 

  132. Sun Y, Dandekar RD, Mao YS, Yin HL, Wulfing C (2011) Phosphatidylinositol (4,5) bisphosphate controls T cell activation by regulating T cell rigidity and organization. PLoS One 6:e27227

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. Muscolini M, Camperio C, Capuano C, Caristi S, Piccolella E, Galandrini R, Tuosto L (2013) Phosphatidylinositol 4-phosphate 5-kinase alpha activation critically contributes to CD28-dependent signaling responses. J Immunol 190:5279–5286

    Article  CAS  PubMed  Google Scholar 

  134. Celli S, Lemaitre F, Bousso P (2007) Real-time manipulation of T cell-dendritic cell interactions in vivo reveals the importance of prolonged contacts for CD4+ T cell activation. Immunity 27:625–634

    Article  CAS  PubMed  Google Scholar 

  135. Huppa JB, Gleimer M, Sumen C, Davis MM (2003) Continuous T cell receptor signaling required for synapse maintenance and full effector potential. Nat Immunol 4:749–755

    Article  CAS  PubMed  Google Scholar 

  136. Iezzi G, Karjalainen K, Lanzavecchia A (1998) The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8:89–95

    Article  CAS  PubMed  Google Scholar 

  137. Kinashi T (2005) Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol 5:546–559

    Article  CAS  PubMed  Google Scholar 

  138. Bolomini-Vittori M, Montresor A, Giagulli C, Staunton D, Rossi B, Martinello M, Constantin G, Laudanna C (2009) Regulation of conformer-specific activation of the integrin LFA-1 by a chemokine-triggered Rho signaling module. Nat Immunol 10:185–194

    Article  CAS  PubMed  Google Scholar 

  139. Wernimont SA, Legate KR, Simonson WT, Fassler R, Huttenlocher A (2010) PIPKI gamma 90 negatively regulates LFA-1-mediated adhesion and activation in antigen-induced CD4+ T cells. J Immunol 185:4714–4723

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  140. Kaga S, Ragg S, Rogers KA, Ochi A (1998) Stimulation of CD28 with B7-2 promotes focal adhesion-like contacts where Rho family small G proteins accumulate in T cells. J Immunol 160:24–27

    CAS  PubMed  Google Scholar 

  141. Kaga S, Ragg S, Rogers KA, Ochi A (1998) Activation of p21-CDC42/Rac-activated kinases by CD28 signaling: p21-activated kinase (PAK) and MEK kinase 1 (MEKK1) may mediate the interplay between CD3 and CD28 signals. J Immunol 160:4182–4189

    CAS  PubMed  Google Scholar 

  142. Michel F, Attal-Bonnefoy G, Mangino G, Mise-Omata S, Acuto O (2001) CD28 as a molecular amplifier extending TCR ligation and signaling capabilities. Immunity 15:935–945

    Article  CAS  PubMed  Google Scholar 

  143. Tavano R, Contento RL, Baranda SJ, Soligo M, Tuosto L, Manes S, Viola A (2006) CD28 interaction with filamin-A controls lipid raft accumulation at the T-cell immunological synapse. Nat Cell Biol 8:1270–1276

    Article  CAS  PubMed  Google Scholar 

  144. Villalba M, Coudronniere N, Deckert M, Teixeiro E, Mas P, Altman A (2000) A novel functional interaction between Vav and PKCtheta is required for TCR-induced T cell activation. Immunity 12:151–160

    Article  CAS  PubMed  Google Scholar 

  145. Salazar-Fontana LI, Barr V, Samelson LE, Bierer BE (2003) CD28 engagement promotes actin polymerization through the activation of the small Rho GTPase Cdc42 in human T cells. J Immunol 171:2225–2232

    Article  CAS  PubMed  Google Scholar 

  146. Tan YX, Manz BN, Freedman TS, Zhang C, Shokat KM, Weiss A (2014) Inhibition of the kinase Csk in thymocytes reveals a requirement for actin remodeling in the initiation of full TCR signaling. Nat Immunol 15:186–194

    Article  CAS  PubMed  Google Scholar 

  147. Boomer JS, Green JM (2010) An enigmatic tail of CD28 signaling. Cold Spring Harb Perspect Biol 2:a002436

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  148. Tuosto L (2011) NF-kappaB family of transcription factors: biochemical players of CD28 co-stimulation. Immunol Lett 135:1–9

    Article  CAS  PubMed  Google Scholar 

  149. Tybulewicz VLJ (2005) Vav-family proteins in T-cell signalling. Curr Opin Immunol 17:267–274

    Article  CAS  PubMed  Google Scholar 

  150. Muscolini M, Camperio C, Porciello N, Caristi S, Capuano C, Viola A, Galandrini R, Tuosto L (2015) Phosphatidylinositol 4-phosphate 5-kinase α and Vav1 mutual cooperation in CD28-mediated actin remodeling and signaling functions. J Immunol 194:1323–1333

    Article  CAS  PubMed  Google Scholar 

  151. Hodson DJ, Turner M (2009) The role of PI3K signalling in the B cell response to antigen. Adv Exp Med Biol 633:43–53

    Article  CAS  PubMed  Google Scholar 

  152. Limon JJ, Fruman DA (2010) B cell receptor signaling: picky about PI3Ks. Sci Signal 3:pe25

    Article  PubMed  CAS  Google Scholar 

  153. Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, Christensson B, Berglof A, Vihinen M, Nore BF, Smith CI (2009) Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev 228:58–73

    Article  CAS  PubMed  Google Scholar 

  154. Thomas JD, Sideras P, Smith CI, Vorechovsky I, Chapman V, Paul WE (1993) Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 261:355–358

    Article  CAS  PubMed  Google Scholar 

  155. Saito K, Tolias KF, Saci A, Koon HB, Humphries LA, Scharenberg A, Rawlings DJ, Kinet JP, Carpenter CL (2003) BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity. Immunity 19:669–678

    Article  CAS  PubMed  Google Scholar 

  156. Carpenter CL (2004) Btk-dependent regulation of phosphoinositide synthesis. Biochem Soc Trans 32:326–329

    Article  CAS  PubMed  Google Scholar 

  157. Kurosaki T (2011) Regulation of BCR signaling. Mol Immunol 48:1287–1291

    Article  CAS  PubMed  Google Scholar 

  158. Walmsley MJ, Ooi SK, Reynolds LF, Smith SH, Ruf S, Mathiot A, Vanes L, Williams DA, Cancro MP, Tybulewicz VL (2003) Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Science 302:459–462

    Article  CAS  PubMed  Google Scholar 

  159. Inabe K, Ishiai M, Scharenberg AM, Freshney N, Downward J, Kurosaki T (2002) Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation. J Exp Med 195:189–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  160. Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT (1996) C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271:348–350

    Article  CAS  PubMed  Google Scholar 

  161. Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF (1995) Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3:39–50

    Article  CAS  PubMed  Google Scholar 

  162. Tuveson DA, Carter RH, Soltoff SP, Fearon DT (1993) CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-kinase. Science 260:986–989

    Article  CAS  PubMed  Google Scholar 

  163. O’Rourke LM, Tooze R, Turner M, Sandoval DM, Carter RH, Tybulewicz VL, Fearon DT (1998) CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vav. Immunity 8:635–645

    Article  PubMed  Google Scholar 

  164. Weng WK, Jarvis L, LeBien TW (1994) Signaling through CD19 activates Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors. J Biol Chem 269:32514–32521

    CAS  PubMed  Google Scholar 

  165. Saci A, Carpenter CL (2005) RhoA GTPase regulates B cell receptor signaling. Mol Cell 17:205–214

    Article  CAS  PubMed  Google Scholar 

  166. Semenas J, Hedlbom A, Miftakhova RR, Sarwar M, Larsson R, Shcherbina L, Johansson ME, Härkönen P, Sterner O, Persson J (2014) The role of PI3K/AKT-related PIP5K1a and the discovery of its selective inhibitor for treatment of advanced prostate cancer. Proc Natl Acad Sci USA 111:E3689–E3698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Italian Association for Cancer Research (AIRC and AIRC 5 × 1000), the Italian Ministry for University and Research (MIUR), the Center of Excellence (BEMM) and the Fondazione Italiana Sclerosi Multipla (Project No. FISM 2011/R/36).

Author information

Authors and Affiliations

  1. Department of Biology and Biotechnology “Charles Darwin”, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, Via dei Sardi 70, 00185, Rome, Italy

    Loretta Tuosto & Michela Muscolini

  2. Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00185, Rome, Italy

    Cristina Capuano & Ricciarda Galandrini

  3. Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, Viale Regina Elena 291, 00185, Rome, Italy

    Angela Santoni

Authors
  1. Loretta Tuosto
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Cristina Capuano
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Michela Muscolini
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Angela Santoni
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Ricciarda Galandrini
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence to Loretta Tuosto or Ricciarda Galandrini.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tuosto, L., Capuano, C., Muscolini, M. et al. The multifaceted role of PIP2 in leukocyte biology. Cell. Mol. Life Sci. 72, 4461–4474 (2015). https://doi.org/10.1007/s00018-015-2013-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-2013-0

Keywords