PI3K isoforms as drug targets in inflammatory diseases: Lessons from pharmacological and genetic strategies

Current Opinion in Investigational Drugs

Volumn 10, Issue 11, 2009, Pages 1151-1162

  Harris, S J ^a   Foster, J G ^a   Ward, S G ^a  

^a University of Bath   (United Kingdom)

Author keywords

Adaptive immunity; Autoimmune disease; Inflammation; Innate immunity; Myocardial infarction; PI3K

Indexed keywords

2 (6 AMINO 9 PURINYLMETHYL) 5 METHYL 3 (2 METHYLPHENYL) 3H QUINAZOLIN 4 ONE; 2 MORPHOLINO 8 PHENYLCHROMONE; 5 (6 QUINOXALINYLMETHYLENE) 2,4 THIAZOLIDINEDIONE; AS 604850; CAL 101; CAL 263; INK 055; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; TG 100 115; TG 101 110; UNCLASSIFIED DRUG; WORTMANNIN;

ADAPTIVE IMMUNITY; ALLERGIC RHINITIS; ARTHRITIS; ASTHMA; ATHEROSCLEROSIS; B CELL LYMPHOMA; CLINICAL TRIAL; DRUG DOSE ESCALATION; DRUG MECHANISM; DRUG STRUCTURE; DRUG TARGETING; ENZYME INHIBITION; FOLLICULAR LYMPHOMA; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HUMAN; INFLAMMATION; INNATE IMMUNITY; NONHUMAN; PROTEIN FUNCTION; PROTEIN TARGETING; REPERFUSION INJURY; REVIEW; RHEUMATOID ARTHRITIS;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; ANTI-INFLAMMATORY AGENTS; CELL MOVEMENT; DRUG DELIVERY SYSTEMS; GENE TARGETING; HUMANS; INFLAMMATION; ISOENZYMES;

EID: 70449368599     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (119)

1. Courtneidge SA, Heber A: An 81 kd protein complexed with middle T antigen and pp60c-src: A possible phosphatidylinositol kinase. Cell (1987) 50(7):1031-1037.
2. Whitman M, Downes CP, Keeler M, Keller T, Cantley L: Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature (1988) 332(6165):644-646.
3. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB: Exploiting the PI3K/ AKT pathway for cancer drug discovery. Nat Rev Drug Discov (2005) 4(12):988-1004.
4. Rommel C, Camps M, Ji H: PI3KS and PI3Ky: Partners in crime in infammation in rheumatoid arthritis and beyond? Nat Rev Immunol (2007) 7(3):191-201.
5. Rückle T, Schwarz MK, Rommel C: PI3Ky inhibition: Towards an 'aspirin of the 21st century'? Nat Rev Drug Discov (2006) 5(11):903-918.
6. Deane JA, Fruman DA: Phosphoinositide 3-kinase: Diverse roles in immune cell activation. Annu Rev Immunol (2004) 22:563-598.
7. Ward SG, Cantrell DA: Phosphoinositide 3-kinases in T lymphocyte activation. Curr Opin Immunol (2001) 13(3):332-338.
8. Suire S, Coadwell J, Ferguson GJ, Davidson K, Hawkins P, Stephens L: p84, a new G| -activated regulatory subunit of the type IB phosphoinositide 3-kinase p110y. Curr Biol (2005) 15(6):566-570.
9. Voigt P, Dorner MB, Schaefer M: Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase y that is highly expressed in heart and interacts with PDE B. J Biol Chem (2006) 281(15):9977-9986.
10. Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, Vanhaesebroeck B: The p110p isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110y. Proc Natl Acad Sci USA (2008) 105(24): 8292-8297.
11. Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC: Signalling by PI3K isoforms: Insights from gene-targeted mice. Trends Biochem Sci (2005) 30(4):194-204.
12. Ward SG: Do phosphoinositide 3-kinases direct lymphocyte navigation? Trends Immunol (2004) 25(2):67-74.
13. Harris SJ, Parry RV, Westwick J, Ward SG: Phosphoinositide lipid phosphatases: Natural regulators of phosphoinositide 3-kinase signaling in T lymphocytes. J Biol Chem (2008) 283(5): 2465-2469.
14. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R et al: Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell (2002) 110(6):737-749.
15. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L et al: PI3Ky modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell (2004) 118(3):375-387.
16. Kok K, Nock GE, Verrall EA, Mitchell MP, Hommes DW, Peppelenbosch MP, Vanhaesebroeck B: Regulation of p110 PI 3-kinase gene expression. PLoS One (2009) 4(4):e5145.
17. Sawyer C, Sturge J, Bennett DC, O'Hare MJ, Allen WE, Bain J, Jones GE, Vanhaesebroeck B: Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110S. Cancer Res (2003) 63(7):1667-1675.
18. Tanigaki K, Mineo C, Yuhanna IS, Chambliss KL, Quon MJ, Bonvini E, Shaul PW: C-reactive protein inhibits insulin activation of endothelial nitric oxide synthase via the immunoreceptor tyrosine-based inhibition motif of Fc RIIB and SHIP-1. Circ Res (2009) 104(11):1275-1282.
19. Fruman DA, Bismuth G: Fine tuning the immune response with PI3K. Immunol Rev (2009) 228(1):253-272.
20. Crabbe T, Welham MJ, Ward SG: The PI3K inhibitor arsenal: Choose your weapon! Trends Biochem Sci (2007) 32(10):450-456.
21. Tarasenko T, Kole HK, Chi AW, Mentink-Kane MM, Wynn TA, Bolland S: T cell-specifc deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses. Proc Natl Acad Sci USA (2007) 104(27):11382-11387.
22. Helgason CD, Damen JE, Rosten P, Grewal R, Sorensen P, Chappel SM, Borowski A, Jirik F, Krystal G, Humphries RK: Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev (1998) 12(11):1610-1620. (Pubitemid 28299513)
23. Collazo MM, Wood D, Paraiso KHT, Lund E, Engelman RW, Le C-T, Stauch D, Kotsch K, Kerr WG: SHIP limits immunoregulatory capacity in the T-cell compartment. Blood (2009) 113(13): 2934-2944.
24. Locke NR, Patterson SJ, Hamilton MJ, Sly LM, Krystal G, Levings MK: SHIP regulates the reciprocal development of T regulatory and Th17 Cells. J Immunol (2009) 183(2):975-983.
25. Condliffe AM, Davidson K, Anderson KE, Ellson CD, Crabbe T, Okkenhaug K, Vanhaesebroeck B, Turner M, Webb L, Wymann MP, Hirsch E et al: Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. Blood (2005) 106(4):1432-1440.
26. Ward SG, Marelli-Berg FM: Mechanisms of chemokine and antigen-dependent T-lymphocyte navigation. Biochem J (2009) 418(1):13-27.
27. Laffargue M, Calvez R, Finan P, Triflieff A, Barbier M, Altruda F, Hirsch E, Wymann MP: Phosphoinositide 3-kinase ? is an essential amplifer of mast cell function. Immunity (2002) 16(3):441-451.
28. Ali K, Camps M, Pearce WP, Ji H, Rückle T, Kuehn N, Pasquali C, Chabert C, Rommel C, Vanhaesebroeck B: Isoform-specifc functions of phosphoinositide 3-kinases: p110? but not p110? promotes optimal allergic responses in vivo. J Immunol (2008) 180(4):2538-2544.
29. Ji H, Rintelen F, Waltzinger C, Bertschy Meier D, Bilancio A, Pearce W, Hirsch E, Wymann MP, Rückle T, Camps M, Vanhaesebroeck B et al: Inactivation of PI3K? and PI3K? distorts T-cell development and causes multiple organ infammation. Blood (2007) 110(8):2940-2947.
30. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL: Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell (2000) 6(4):909-919.
31. Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE: Essential role of phosphoinositide 3-kinase ? in neutrophil directional movement. J Immunol (2003) 170(5):2647-2654.
32. Camps M, Rückle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Francon B, Martin T et al: Blockade of PI3K? suppresses joint infammation and damage in mouse models of rheumatoid arthritis. Nat Med (2005) 11(9):936-943.
33. Doukas J, Wrasidlo W, Noronha G, Dneprovskaia E, Fine R, Weis S, Hood J, Demaria A, Soll R, Cheresh D: Phosphoinositide 3-kinase ?/? inhibition limits infarct size after myocardial ischemia/ reperfusion injury. Proc Natl Acad Sci USA (2006) 103(52): 19866-19871.
34. Medina-Tato DA, Ward SG, Watson ML: Phosphoinositide 3-kinase signalling in lung disease: Leucocytes and beyond. Immunology (2007) 121(4):448-461.
35. Nashed BF, Zhang T, Al-Alwan M, Srinivasan G, Halayko AJ, Okkenhaug K, Vanhaesebroeck B, Hayglass KT, Marshall AJ: Role of the phosphoinositide 3-kinase p110? in generation of type 2 cytokine responses and allergic airway infammation. Eur J Immunol (2007) 37(2):416-424.
36. Lee KS, Lee HK, Hayfick JS, Lee YC, Puri KD: Inhibition of phosphoinositide 3-kinase ? attenuates allergic airway infammation and hyperresponsiveness in murine asthma model. FASEB J (2006) 20(3):455-465.
37. Farghaly HSM, Blagbrough IS, Medina-Tato DA, Watson ML: Interleukin 13 increases contractility of murine tracheal smooth muscle by a phosphoinositide 3-kinase p110?-dependent mechanism. Mol Pharmacol (2008) 73(5):1530-1537.
38. Lim DH, Cho JY, Song DJ, Lee SY, Miller M, Broide DH: PI3K ?-defcient mice have reduced levels of allergen-induced eosinophilic infammation and airway remodeling. Am J Physiol Lung Cell Mol Physiol (2009) 296(2):L210-L219.
39. Takeda M, Ito W, Tanabe M, Ueki S, Kato H, Kihara J, Tanigai T, Chiba T, Yamaguchi K, Kayaba H, Imai Y et al: Allergic airway hyperresponsiveness, infammation, and remodeling do not develop in phosphoinositide 3-kinase ?-defcient mice. J Allergy Clin Immunol (2009) 123(4):805-812.
40. Thomas M, Edwards MJ, Sawicka E, Duggan N, Hirsch E, Wymann MP, Owen C, Triflieff A, Walker C, Westwick J, Finan P: Essential role of phosphoinositide 3-kinase ? in eosinophil chemotaxis within acute pulmonary infammation. Immunology (2009) 126(3):413-422.
41. Pinho V, de Castro Russo R, Amaral FA, de Sousa LP, Barsante MM, de Souza DG, Alves-Filho JC, Cara DC, Hayfick JS, Rommel C, Rückle T et al: Tissue- and stimulus-dependent role of phosphatidylinositol 3-kinase isoforms for neutrophil recruitment induced by chemoattractants in vivo. J Immunol (2007) 179(11):7891-7898.
42. Doukas J, Eide L, Stebbins K, Racanelli-Layton A, Dellamary L, Martin M, Dneprovskaia E, Noronha G, Soll R, Wrasidlo W, Acevedo LM et al: Aerosolized phosphoinositide 3-kinase ?/? inhibitor TG100-115 [3-[2,4-diamino-6-(3- hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease. J Pharmacol Exp Ther (2009) 328(3):758-765.
43. Thomas MJ, Smith A, Head DH, Milne L, Nicholls A, Pearce W, Vanhaesebroeck B, Wymann MP, Hirsch E, Triflieff A, Walker C et al: Airway infammation: Chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases. Eur J Immunol (2005) 35(4):1283-1291.
44. Yum HK, Arcaroli J, Kupfner J, Shenkar R, Penninger JM, Sasaki T, Yang KY, Park JS, Abraham E: Involvement of phosphoinositide 3-kinases in neutrophil activation and the development of acute lung injury. J Immunol (2001) 167(11):6601-6608.
45. Kuroiwa T, Lee EG: Cellular interactions in the pathogenesis of lupus nephritis: The role of T cells and macrophages in the amplifcation of the infammatory process in the kidney. Lupus (1998) 7(9):597-603.
46. Wakeland EK, Wandstrat AE, Liu K, Morel L: Genetic dissection of systemic lupus erythematosus. Curr Opin Immunol (1999) 11(6):701-707.
47. Barber DF, Bartolome A, Hernandez C, Flores JM, Fernandez-Arias C, Rodriguez-Borlado L, Hirsch E, Wymann M, Balomenos D, Carrera AC: Class IB-phosphatidylinositol 3-kinase (PI3K) defciency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion. J Immunol (2006) 176(1):589-593.
48. Barber DF, Bartolomé A, Hernandez C, Flores JM, Redondo C, Fernandez-Arias C, Camps M, Rückle T, Schwarz MK, Rodriguez S, Martinez-A C et al: PI3K? inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat Med (2005) 11(9):933-935.
49. Smolen JS, Steiner G: Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov (2003) 2(6):473-488.
50. Randis TM, Puri KD, Zhou H, Diacovo TG: Role of PI3K? and PI3K? in infammatory arthritis and tissue localization of neutrophils. Eur J Immunol (2008) 38(5):1215-1224.
51. Crow MT, Mani K, Nam YJ, Kitsis RN: The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res (2004) 95(10):957-970.
52. Frangogiannis NG, Smith CW, Entman ML: The infammatory response in myocardial infarction. Cardiovasc Res (2002) 53(1):31-47.
53. Hansson GK, Libby P: The immune response in atherosclerosis: A double-edged sword. Nat Rev Immunol (2006) 6(7):508-519.
54. Fougerat A, Gayral S, Gourdy P, Schambourg A, Rückle T, Schwarz MK, Rommel C, Hirsch E, Arnal JF, Salles JP, Perret B et al: Genetic and pharmacological targeting of phosphoinositide 3-kinase-? reduces atherosclerosis and favors plaque stability by modulating infammatory processes. Circulation (2008) 117(10):1310-1317.
55. Chang JD, Sukhova GK, Libby P, Schvartz E, Lichtenstein AH, Field SJ, Kennedy C, Madhavarapu S, Luo J, Wu D, Cantley LC: Deletion of the phosphoinositide 3-kinase p110? gene attenuates murine atherosclerosis. Proc Natl Acad Sci USA (2007) 104(19):8077-8082.
56. Fukao T, Koyasu S: PI3K and negative regulation of TLR signaling. Trends Immunol (2003) 24(7):358-363.
57. Fukao T, Tanabe M, Terauchi Y, Ota T, Matsuda S, Asano T, Kadowaki T, Takeuchi T, Koyasu S: PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol (2002) 3(9):875-881.
58. Fukao T, Yamada T, Tanabe M, Terauchi Y, Ota T, Takayama T, Asano T, Takeuchi T, Kadowaki T, Hata Ji J, Koyasu S: Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-defcient mice. Nat Immunol (2002) 3(3):295-304.
59. Maus UA, Backi M, Winter C, Srivastava M, Schwarz MK, Rückle T, Paton JC, Briles D, Mack M, Welte T, Maus R et al: Importance of phosphoinositide 3-kinase ? in the host defense against pneumococcal infection. Am J Respir Crit Care Med (2007) 175(9):958-966.
60. Tang Q, Bluestone JA: The Foxp3+ regulatory T cell: A jack of all trades, master of regulation. Nat Immunol (2008) 9(3):239-244.
61. Vignali DA, Collison LW, Workman CJ: How regulatory T cells work. Nat Rev Immunol (2008) 8(7):523-532.
62. Patton DT, Garden OA, Pearce WP, Clough LE, Monk CR, Leung E, Rowan WC, Sancho S, Walker LSK, Vanhaesebroeck B, Okkenhaug K: Cutting edge: The phosphoinositide 3-kinase p110? is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J Immunol (2006) 177(10):6598-6602.
63. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfeld MD, Smith AJ et al: Impaired B and T cell antigen receptor signaling in p110? PI 3-kinase mutant mice. Science (2002) 297(5583):1031-1034.
64. Calistoga Pharmaceuticals reports additional clinical responses in ongoing clinical trial of CAL-101, an isoform-selective PI3K inhibitor, under evaluation in patients with hematologic malignancies: Calistoga Pharmaceuticals Inc, Seattle, WA, USA (2009). www.calistogapharma.com/pdf/ CalistogaPharma%20%20EHA%20release-06-06-09.pdf
65. Flinn IW, Byrd JC, Furman RR, Brown JR, Lin TS, Bello C, Giese NA, Yu AS: Preliminary evidence of clinical activity in a phase I study of CAL-101, a selective inhibitor of the p110S isoform of phosphatidylinositol 3-kinase (PI3K), in patients with select hematologic malignancies. J Clin Oncol (2009) 27(15 Suppl): Abs 3543.
66. Nienaber JJ, Tachibana H, Naga Prasad SV, Esposito G, Wu D, Mao L, Rockman HA: Inhibition of receptor-localized PI3K preserves cardiac p-adrenergic receptor function and ameliorates pressure overload heart failure. J Clin Invest (2003) 112(7):1067-1079.
67. Perrino C, Naga Prasad SV, Schroder JN, Hata JA, Milano C, Rockman HA: Restoration of p-adrenergic receptor signaling and contractile function in heart failure by disruption of the pARK1/phosphoinositide 3-kinase complex. Circulation (2005) 111(20):2579-2587.
68. Hirsch E, Braccini L, Ciraolo E, Morello F, Perino A: Twice upon a time: PI3K's secret double life exposed. Trends Biochem Sci (2009) 34(5):244-248.
69. Burma S, Chen DJ: Role of DNA-PK in the cellular response to DNA double-strand breaks. DNA Repair (2004) 3(8-9):909-918.
70. Collis SJ, DeWeese TL, Jeggo PA, Parker AR: The life and death of DNA-PK. Oncogene (2005) 24(6):949-961.
71. Janes MR, Fruman DA: Immune regulation by rapamycin: Moving beyond T cells. Sci Signal (2009) 2(67):pe25.
72. Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B: The p110S isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol (2006) 177(8):5122-5128.
73. Jarmin SJ, David R, Ma L, Chai JG, Dewchand H, Takesono A, Ridley AJ, Okkenhaug K, Marelli-Berg FM: T cell receptor-induced phosphoinositide-3-kinase p110S activity is required for T cell localization to antigenic tissue in mice. J Clin Invest (2008) 118(3):1154-1164.
74. Rodriguez-Borlado L, Barber DF, Hernandez C, Rodriguez-Marcos MA, Sanchez A, Hirsch E, Wymann M, Martinez-A C, Carrera AC: Phosphatidylinositol 3-kinase regulates the CD4/CD8 T cell differentiation ratio. J Immunol (2003) 170(9):4475-4482.
75. Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I, Joza N et al: Function of PI3K in thymocyte development, T cell activation, and neutrophil migration. Science (2000) 287(5455):1040-1046.
76. Alcazar I, Marques M, Kumar A, Hirsch E, Wymann M, Carrera AC, Barber DF: Phosphoinositide 3 kinase y participates in T cell receptor induced T cell activation. J Exp Med (2007) 204(12):2977-2987.
77. Nombela-Arrieta C, Lacalle RA, Montoya MC, Kunisaki Y, MegIas D, Marqués M, Carrera AC, Mañes S, Fukui Y, Martinez-A C, Stein JV: Differential requirements for DOCK2 and phosphoinositide-3 kinase y during T and B lymphocyte homing. Immunity (2004) 21(3):429-441.
78. Thomas MS, Mitchell JS, DeNucci CC, Martin AL, Shimizu Y: The p110y isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral infammatory sites. J Leukocyte Biol (2008) 84(3):814-823.
79. Oh SY, Zheng T, Bailey ML, Barber DL, Schroeder JT, Kim YK, Zhu Z: Src homology 2 domain-containing inositol 5-phosphatase 1 defciency leads to a spontaneous allergic infammation in the murine lung. J Allergy Clin Immunol (2007) 119(1):123-131.
80. Kashiwada M, Cattoretti G, McKeag L, Rouse T, Showalter BM, Al-Alem U, Niki M, Pandolf PP, Field EH, Rothman PB: Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5'-phosphatase are required for regulation of CD4 CD25 T Cell development. J Immunol (2006) 176(7):3958-3965.
81. Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolf PP: Impaired Fas response and autoimmunity in PTEN+/- mice. Science (1999) 285(5436):2122-2125.
82. Lacalle RA, Gomez-Mouton C, Barber DF, Jimenez-Baranda S, Mira E, Martinez-A C, Carrera AC, Manes S: PTEN regulates motility but not directionality during leukocyte chemotaxis. J Cell Sci (2004) 117(25):6207-6215.
83. Johnson TA, Tsutsui S, Jirik FR: Antigen-induced PTEN gene deletion in T cells exacerbates neuropathology in experimental autoimmune encephalomyelitis. Am J Pathol (2008) 172(4): 980-992.
84. Buckler JL, Walsh PT, Porrett PM, Choi Y, Turka LA: T cell requirement for CD28 costimulation is due to negative regulation of TCR signals by PTEN. J Immunol (2006) 177(7):4262-4266.
85. Zhang T-T, Okkenhaug K, Nashed BF, Puri KD, Knight ZA, Shokat KM, Vanhaesebroeck B, Marshall AJ: Genetic or pharmaceutical blockade of p110? phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol (2008) 122(4):811-819.e2.
86. Al-Alwan MM, Okkenhaug K, Vanhaesebroeck B, Hayfick JS, Marshall AJ: Requirement for phosphoinositide 3-kinase p110? signaling in B cell antigen receptor-mediated antigen presentation. J Immunol (2007) 178(4):2328-2335.
87. Bilancio A, Okkenhaug K, Camps M, Emery JL, Rückle T, Rommel C, Vanhaesebroeck B: Key role of the p110? isoform of PI3K in B-cell antigen and IL-4 receptor signaling: Comparative analysis of genetic and pharmacologic interference with p110? function in B cells. Blood (2006) 107(2):642-650.
88. Helgason CD, Kalberer CP, Damen JE, Chappel SM, Pineault N, Krystal G, Humphries RK: A dual role for Src homology 2 domain-containing inositol-5-phosphatase (SHIP) in immunity: Aberrant development and enhanced function of B lymphocytes in SHIP-/- mice. J Exp Med (2000) 191(5):781-794.
89. Leung WH, Tarasenko T, Bolland S: Differential roles for the inositol phosphatase SHIP in the regulation of macrophages and lymphocytes. Immunol Res (2009) 43(1-3):243-251.
90. Suzuki A, Kaisho T, Ohishi M, Tsukio-Yamaguchi M, Tsubata T, Koni PA, Sasaki T, Mak TW, Nakano T: Critical roles of PTEN in B cell homeostasis and immunoglobulin class switch recombination. J Exp Med (2003) 197(5):657-667.
91. Sarraj B, Massberg S, Li Y, Kasorn A, Subramanian K, Loison F, Silberstein LE, von Andrian U, Luo HR: Myeloid-specifc deletion of tumor suppressor PTEN augments neutrophil transendothelial migration during Infammation. J Immunol (2009) 182(11): 7190-7200.
92. Heit B, Robbins SM, Downey CM, Guan Z, Colarusso P, Miller BJ, Jirik FR, Kubes P: PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils. Nat Immunol (2008) 9(7):743-752.
93. Li Y, Jia Y, Pichavant M, Loison F, Sarraj B, Kasorn A, You J, Robson BE, Umetsu DT, Mizgerd JP, Ye K, Luo HR: Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia- associated pneumonia. Blood (2009) 113(20):4930-4941.
94. Papakonstanti EA, Zwaenepoel O, Bilancio A, Burns E, Nock GE, Houseman B, Shokat K, Ridley AJ, Vanhaesebroeck B: Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages. J Cell Sci (2008) 121(Pt 24):4124-4133.
95. Jones GE, Prigmore E, Calvez R, Hogan C, Dunn GA, Hirsch E, Wymann MP, Ridley AJ: Requirement for PI 3-kinase ? in macrophage migration to MCP-1 and CSF-1. Exp Cell Res (2003) 290(1):120-131.
96. Bishop JL, Sly LM, Krystal G, Finlay BB: The inositol phosphatase SHIP controls Salmonella enterica Serovar Typhimurium infection in vivo. Infect Immun (2008) 76(7):2913-2922.
97. Nakamura K, Malykhin A, Coggeshall KM: The Src homology 2 domain-containing inositol 5-phosphatase negatively regulates Fc? receptor-mediated phagocytosis through immunoreceptor tyrosine-based activation motif-bearing phagocytic receptors. Blood (2002) 100(9):3374-3382.
98. Kamen LA, Levinsohn J, Cadwallader A, Tridandapani S, Swanson JA: SHIP-1 increases early oxidative burst and regulates phagosome maturation in macrophages. J Immunol (2008) 180(11):7497-7505.
99. Ali K, Bilancio A, Thomas M, Pearce W, Gilfllan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R et al: Essential role for the p110S phosphoinositide 3-kinase in the allergic response. Nature (2004) 431(7011):1007-1011.
100. Kitaura J, Kinoshita T, Matsumoto M, Chung S, Kawakami Y, Leitges M, Wu D, Lowell CA, Kawakami T: IgE- and IgE+ Ag-mediated mast cell migration in an autocrine/paracrine fashion. Blood (2005) 105(8):3222-3229.
101. Haddon DJ, Antignano F, Hughes MR, Blanchet M-R, Zbytnuik L, Krystal G, McNagny KM: SHIP1 is a repressor of mast cell hyperplasia, cytokine production, and allergic infammation in vivo. J Immunol (2009) 183(1):228-236.
102. Huber M, Helgason CD, Damen JE, Liu L, Humphries RK, Krystal G: The src homology 2-containing inositol phosphatase (SHIP) is the gatekeeper of mast cell degranulation. Proc Natl Acad Sci USA (1998) 95(19):11330-11335.
103. Furumoto Y, Brooks S, Olivera A, Takagi Y, Miyagishi M, Taira K, Casellas R, Beaven MA, Gilfllan AM, Rivera J: Lentiviral short hairpin RNA silencing of PTEN in human mast cells reveals constitutive signals that promote cytokine secretion and cell survival. J Immunol (2006) 176(9):5167-5171.
104. Saudemont A, Garcon F, Yadi H, Roche-Molina M, Kim N, Segonds-Pichon A, Martin-Fontecha A, Okkenhaug K, Colucci F: p110 and p110S isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. Proc Natl Acad Sci USA (2009) 106(14):5795-5800.
105. Tassi I, Cella M, Gilfllan S, Turnbull I, Diacovo TG, Penninger JM, Colonna M: p110 and p110S phosphoinositide 3-kinase signaling pathways synergize to control development and functions of murine NK cells. Immunity (2007) 27(2):214-227.
106. Wang J-W, Howson JM, Ghansah T, Desponts C, Ninos JM, May SL, Nguyen KHT, Toyama-Sorimachi N, Kerr WG: Infuence of SHIP on the NK repertoire and allogeneic bone marrow transplantation. Science (2002) 295(5562):2094-2097.
107. Kishimoto H, Ohteki T, Yajima N, Kawahara K, Natsui M, Kawarasaki S, Hamada K, Horie Y, Kubo Y, Arase S, Taniguchi M et al: The PTEN/PI3K pathway governs the homeostasis of V14iNKT cells. Blood (2007) 109(8):3316-3324. (Pubitemid 46572519)
108. Krishnamoorthy N, Oriss TB, Paglia M, Fei M, Yarlagadda M, Vanhaesebroeck B, Ray A, Ray P: Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nat Med (2008) 14(5):565-573.
109. Del Prete A, Vermi W, Dander E, Otero K, Barberis L, Luini W, Bernasconi S, Sironi M, Santoro A, Garlanda C, Facchetti F et al: Defective dendritic cell migration and activation of adaptive immunity in PI3Ky-defcient mice. EMBO J (2004) 23(17): 3505-3515.
110. Neill L, Tien AH, Rey-Ladino J, Helgason CD: SHIP-defcient mice provide insights into the regulation of dendritic cell development and function. Exp Hematol (2007) 35(4):627-639.
111. Agrawal A, Agrawal S, Cao JN, Su H, Osann K, Gupta S: Altered innate immune functioning of dendritic cells in elderly humans: A role of phosphoinositide 3-kinase signaling pathway. J Immunol (2007) 178(11):6912-6922.
112. Vonakis BM, Vasagar K, Gibbons JSP, Gober L, Sterba PM, Chang H, Saini SS: Basophil FcsRI histamine release parallels expression of Src-homology 2-containing inositol phosphatases in chronic idiopathic urticaria. J Allergy Clin Immunol (2007) 119(2):441-448.
113. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T et al: A pharmacological map of the PI3-K family defnes a role for p110 in insulin signaling. Cell (2006) 125(4):733-747.
114. CAL-101 - Clinical proof of concept study ongoing: Calistoga Pharmaceuticals Inc, Seattle, WA, USA (2009). www. calistogapharma.com/products. php.
115. Ikeda H, Hideshima T, Okawa Y, Vallet S, Pozzi S, Santo L, Gorgun G, Fulciniti M, Raje NS, Perrone G, Munshi N et al: CAL-101, a specifc inhibitor of the p110S isoform of phosphatidylinositol 3-kinase induces cytotoxicity in multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts) (2008) 112(11):Abs 2753.
116. May SE, Kashishian A, Lin TS, Jones JA, Flynn JM, Ulrich RG, Chen H, Yu AS, Puri KD, Lannutti BJ, Giese NA et al: CAL-101, a selective inhibitor of the p110 isoform of phosphatidylinositol 3-kinase, effectively induces apoptosis in primary chronic lymphocytic leukemia cells providing a novel therapeutic strategy for the treatment of this disease. Blood (ASH Annual Meeting Abstracts) (2008) 112(11):Abs 3165.
117. Product pipeline: Calistoga Pharmaceuticals Inc, Seattle, WA, USA (2009). www.calistogapharma.com/products.php
118. TargeGen Inc: FDA grants Fast Track designation for TargeGen TG-100-115 cardiovascular compound. Press Release (2006): June 29.
119. Boyle DL, Rommel C, Topolewski K, Firestein GS: A novel PI3Kinase y/S inhibitor suppresses collagen-induced arthritis. ACR/ARHP Annual Scientifc Meeting, Philadelphia, PA, USA (2009) 73:Abs 669.