PI3Kδ and PI3Kγ: Partners in crime in inflammation in rheumatoid arthritis and beyond?

Nature Reviews Immunology

Volumn 7, Issue 3, 2007, Pages 191-201

  Rommel, Christian ^a   Camps, Montserrat ^a   Ji, Hong ^a  

^a MERCK SERONO S A   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ABATACEPT; ANTIINFLAMMATORY AGENT; CALCIUM; CHEMOKINE; HLA DR ANTIGEN; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE DELTA; PHOSPHATIDYLINOSITOL 3 KINASE GAMMA; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN SUBUNIT; T LYMPHOCYTE RECEPTOR; UNCLASSIFIED DRUG; VASCULOTROPIN;

ADAPTIVE IMMUNITY; CALCIUM CELL LEVEL; CALCIUM MOBILIZATION; CD4+ T LYMPHOCYTE; CELL SURVIVAL; CELLULAR DISTRIBUTION; DRUG EFFECT; EXPERIMENTAL MOUSE; HUMAN; IMMUNE FUNCTION TEST; IMMUNE RESPONSE; IMMUNOPATHOGENESIS; IMMUNOPATHOLOGY; INFLAMMATION; INFLAMMATORY DISEASE; MEMORY T LYMPHOCYTE; NONHUMAN; PRIORITY JOURNAL; PROTEIN FAMILY; PROTEIN LOCALIZATION; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; SKIN ANAPHYLAXIS;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; ARTHRITIS, RHEUMATOID; HUMANS; ISOENZYMES; MULTIGENE FAMILY; SIGNAL TRANSDUCTION;

EID: 33847239467     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri2036     Document Type: Review

References (128)

1. Fishman, M. C. & Porter, J. A. Pharmaceuticals: a new grammar for drug discovery. Nature 437, 491-493 (2005).
2. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655-1657 (2002).
3. Vanhaesebroeck, B. et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 70, 535-602 (2001). An excellent review of the molecular biology and biochemistry of class I PI3Ks.
4. Foster, F. M., Traer, C. J., Abraham, S. M. & Fry, M. J. The phosphoinositide (PI) 3-kinase family. J. Cell Sci. 116, 3037-3040 (2003).
5. Brachmann, S. M. et al. Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement. Mol. Cell. Biol. 25, 2593-2606 (2005).
6. Fruman, D. A. & Cantley, L. C. Phosphoinositide 3-kinase in immunological systems. Semin. Immunol. 14, 7-18 (2002). A comprehensive review of the regulation, function and receptor signalling of class I PI3Ks (in leukocytes).
7. Jimenez, C., Hernandez, C., Pimentel, B. & Carrera, A. C. The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras. J. Biol. Chem. 277, 41556-41562 (2002).
8. Vanhaesebroeck, B., Ali, K., Bilancio, A., Geering, B. & Foukas, L. C. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem. Sci. 30, 194-204 (2005).
9. Voigt, P., Dorner, M. B. & Schaefer, M. Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase γ that is highly expressed in heart and interacts with PDE3B. J. Biol. Chem. 281, 9977-9986 (2006).
10. Stephens, L. R. et al. The G βγ sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89, 105-114 (1997).
11. Suire, S. et al. p84, a new Gβγ-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110?. Curr. Biol. 15, 566-570 (2005).
12. Brock, C. et al. Roles of G βγ in membrane recruitment and activation of p110γ/p101 phosphoinositide 3-kinase γ. J. Cell. Biol. 160, 89-99 (2003).
13. Stephens, L. et al. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein βγ subunits. Cell 77, 83-93 (1994).
14. Leopoldt, D. et al. Gβγ stimulates phosphoinositide 3-kinase-γ by direct interaction with two domains of the catalytic p110 subunit. J. Biol. Chem. 273, 7024-7029 (1998).
15. Bernstein, H. G., Keilhoff, G., Reiser, M., Freese, S. & Wetzker, R. Tissue distribution and subcellular localization of a G-protein activated phosphoinositide 3-kinase. An immunohistochemical study. Cell. Mol. Biol. (Noisy-le-grand) 44, 973-983 (1998).
16. Patrucco, E. et al. PI3Kγ modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and-independent effects. Cell 118, 375-387 (2004).
17. Wetzker, R. & Rommel, C. Phosphoinositide 3-kinases as targets for therapeutic intervention. Curr. Pharm. Des. 10, 1915-1922 (2004).
18. Wymann, M. P., Zvelebil, M. & Laffargue, M. Phosphoinositide 3-kinase signalling - which way to target? Trends Pharmacol. Sci. 24, 366-376 (2003).
19. Wymann, M. P. et al. Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol. Cell. Biol. 16, 1722-1733 (1996).
20. Davies, S. P., Reddy, H., Caivano, M. & Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95-105 (2000).
21. Knight, Z. A. et al. Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold. Bioorg. Med. Chem. 12, 4749-4759 (2004).
22. Liu, Y. et al. Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase. Chem. Biol. 12, 99-107 (2005).
23. Clayton, E. et al. A crucial role for the p110δ subunit of phosphatidylinositol 3-kinase in B cell development and activation. J. Exp. Med. 196, 753-763 (2002).
24. Jou, S. T. et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the B-cell receptor complex. Mol. Cell. Biol. 22, 8580-8591 (2002).
25. Okkenhaug, K. et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 1031-1034 (2002). References 23-25 report the important and non-redundant role of PI3Kδ in T-cell and B-cell signalling.
26. Fruman, D. A. et al. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α. Nature Genet. 26, 379-3782 (2000).
27. Garcia, Z., Kumar, A., Marques, M., Cortes, I. & Carrera, A. C. Phosphoinositide 3-kinase controls early and late events in mammalian cell division. EMBO J. 25, 655-661 (2006).
28. Ueki, K. et al. Positive and negative roles of p85α and p85β regulatory subunits of phosphoinositide 3-kinase in insulin signaling. J. Biol. Chem. 278, 48453-48466 (2003).
29. Ueki, K. et al. Increased insulin sensitivity in mice lacking p85β subunit of phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 99, 419-424 (2002).
30. Terauchi, Y. et al. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85α subunit of phosphoinositide 3-kinase. Nature Genet. 21, 230-235 (1999).
31. Vanhaesebroeck, B., Rohn, J. L. & Waterfield, M. D. Gene targeting: attention to detail. Cell 118, 274-276 (2004).
32. Bi, L., Okabe, I., Bernard, D. J. & Nussbaum, R. L. Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase. Mamm. Genome 13, 169-172 (2002).
33. Bi, L., Okabe, I., Bernard, D. J., Wynshaw-Boris, A. & Nussbaum, R. L. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110α subunit of phosphoinositide 3-kinase. J. Biol. Chem. 274, 10963-10968 (1999).
34. Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation. Science 287, 1049-1053 (2000).
35. Li, Z. et al. Roles of PLC-β2 and-β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science 287, 1046-1049 (2000).
36. Sasaki, T. et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040-1046 (2000). References 34-36 report the important and nonredundant role of PI3Kγ in chemokine signalling, leukocyte migration, oxidative burst and T-cell activation and proliferation.
37. Del Prete, A. et al. Defective dendritic cell migration and activation of adaptive immunity in PI3Kγ-deficient mice. EMBO J. 23, 3505-3515 (2004).
38. Ali, K. et al. Essential role for the p110δ phosphoinositide 3-kinase in the allergic response. Nature 431, 1007-1011 (2004). Shows an essential and non-redundant role for PI3Kδ in mast-cell signalling and acute allergic responses.
39. Laffargue, M. et al. Phosphoinositide 3-kinase γ is an essential amplifier of mast cell function. Immunity 16, 441-451 (2002). Shows an essential and non-redundant role for PI3Kγ in mast-cell signalling and acute allergic responses.
40. Ward, S. G. & Finan, P. Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Curr. Opin. Pharmacol. 3, 426-434 (2003).
41. Barber, D. F. et al. PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nature Med. 11, 933-935 (2005).
42. Camps, M. et al. Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nature Med. 11, 936-943 (2005). References 41 and 42 use orally active small-molecule inhibitors of PI3Kγ to validate an important role for PI3Kγ in inflammatory diseases such as SLE and rheumatoid arthritis.
43. Firestein, G. S. Inhibiting inflammation in rheumatoid arthritis. N. Engl. J. Med. 354, 80-82 (2006).
44. Thomas, M. J. et al. Airway inflammation: chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases. Eur. J. Immunol. 35, 1283-1291 (2005).
45. Lee, K. S., Lee, H. K., Hayflick, J. S., Lee, Y. C. & Puri, K. D. Inhibition of phosphoinositide 3-kinase δ attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. FASEB J. 20, 455-465 (2006). References 44 and 45 describe the role of PI3Kδ versus PI3Kγ in airway inflammation.
46. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356-361 (2003).
47. Firestein, G. S. The T cell cometh: interplay between adaptive immunity and cytokine networks in rheumatoid arthritis. J. Clin. Invest. 114, 471-474 (2004).
48. Monach, P. A., Benoist, C. & Mathis, D. The role of antibodies in mouse models of rheumatoid arthritis, and relevance to human disease. Adv. Immunol. 82, 217-248 (2004).
49. Benoist, C. & Mathis, D. A revival of the B cell paradigm for rheumatoid arthritis pathogenesis? Arthritis Res. 2, 90-94 (2000).
50. Weyand, C. M., Seyler, T. M. & Goronzy, J. J. B cells in rheumatoid synovitis. Arthritis Res. Ther. 7 (Suppl. 3), 9-12 (2005).
51. Feldmann, M. et al. Analysis of cytokine expression in rheumatoid synovium has provided new insights into the pathogenesis of rheumatoid arthritis and new therapeutic opportunities. Transplant. Proc. 33, 2085-2086 (2001).
52. Feldmann, M. et al. Cytokine blockade in rheumatoid arthritis. Adv. Exp. Med. Biol. 490, 119-127 (2001).
53. Sarkar, S. & Fox, D. A. Dendritic cells in rheumatoid arthritis. Front Biosci. 10, 656-665 (2005).
54. Benoist, C. & Mathis, D. Mast cells in autoimmune disease. Nature 420, 875-878 (2002).
55. Lee, D. M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689-1692 (2002).
56. Nigrovic, P. A. & Lee, D. M. Mast cells in inflammatory arthritis. Arthritis Res. Ther. 7, 1-11 (2005).
57. Edwards, S. W. & Hallett, M. B. Seeing the wood for the trees: the forgotten role of neutrophils in rheumatoid arthritis. Immunol. Today 18, 320-324 (1997).
58. Wipke, B. T. & Allen, P. M. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J. Immunol. 167, 1601-1608 (2001).
59. Buckner, J. H. & Nepom, G. T. Genetics of rheumatoid arthritis: is there a scientific explanation for the human leukocyte antigen association? Curr. Opin. Rheumatol. 14, 254-259 (2002).
60. Jawaheer, D. et al. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am. J. Hum. Genet. 71, 585-594 (2002).
61. Weyand, C. M., Hicok, K. C., Hunder, G. G. & Goronzy, J. J. The HLA-DRB1 locus as a genetic component in giant cell arteritis. Mapping of a disease-linked sequence motif to the antigen binding site of the HLA-DR molecule. J. Clin. Invest. 90, 2355-2361 (1992).
62. + T cell expansions in normal individuals and patients with rheumatoid arthritis. J. Immunol. 154, 3538-3547 (1995).
63. + T cell population of rheumatoid arthritis patients. J. Immunol. 156, 852-858 (1996).
64. - T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J. Clin. Invest. 97, 2027-2037 (1996).
65. H2 cytokines. J. Immunol. 161, 409-414 (1998).
66. Kremer, J. M. et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 52, 2263-2271 (2005).
67. Ruderman, E. M. & Pope, R. M. The evolving clinical profile of abatacept (CTLA4-Ig): a novel co-stimulatory modulator for the treatment of rheumatoid arthritis. Arthritis Res. Ther. 7 (Suppl 2), 21-25 (2005).
68. Mulherin, D., Fitzgerald, O. & Bresnihan, B. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum. 39, 115-124 (1996).
69. Yanni, G., Whelan, A., Feighery, C. & Bresnihan, B. Synovial tissue macrophages and joint erosion in rheumatoid arthritis. Ann. Rheum. Dis. 53, 39-44 (1994).
70. Gonzalez-Garcia, A. et al. A new role for the p85- phosphatidylinositol 3-kinase regulatory subunit linking FRAP to p70 S6 kinase activation. J. Biol. Chem. 277, 1500-1508 (2002).
71. Jimenez, C. et al. Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J. 17, 743-753 (1998).
72. Rodriguez-Borlado, L. et al. Phosphatidylinositol 3-kinase regulates the CD4/CD8 T cell differentiation ratio. J. Immunol. 170, 4475-4482 (2003).
73. Borlado, L. R. et al. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J. 14, 895-903 (2000).
74. Xu, Y. & Wiernik, P. H. Systemic lupus erythematosus and B-cell hematologic neoplasm. Lupus 10, 841-850 (2001).
75. +/- mice. Science 285, 2122-2125 (1999).
76. Barber, D. F. et al. Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion. J. Immunol. 176, 589-593 (2006).
77. Reif, K. et al. Cutting edge: Differential roles for phosphoinositide 3-kinases, p110γ and p110δ, in lymphocyte chemotaxis and homing. J. Immunol. 173, 2236-2240 (2004).
78. Curnock, A. P., Logan, M. K. & Ward, S. G. Chemokine signalling: pivoting around multiple phosphoinositide 3-kinases. Immunology 105, 125-136 (2002).
79. H cells. J. Immunol. 177, 5122-5128 (2006).
80. + regulatory T cells. J. Immunol. 177, 6598-6602 (2006).
81. Jasin, H. E. Autoantibody specificities of immune complexes sequestered in articular cartilage of patients with rheumatoid arthritis and osteoarthritis. Arthritis Rheum. 28, 241-248 (1985).
82. Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572-2581 (2004).
83. Edwards, J. C. & Cambridge, G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nature Rev. Immunol. 6, 394-403 (2006).
84. Bilancio, A. et al. Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells. Blood 107, 642-650 (2006).
85. Sujobert, P. et al. Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106, 1063-1066 (2005).
86. Schon, M. P. & Boehncke, W. H. Psoriasis. N. Engl. J. Med. 352, 1899-1912 (2005).
87. Cook, H. T. & Botto, M. Mechanisms of disease: the complement system and the pathogenesis of systemic lupus erythematosus. Nature Clin. Pract. Rheumatol. 2, 330-337 (2006).
88. Shapiro, S. D. COPD unwound. N. Engl. J. Med. 352, 2016-2019 (2005).
89. Caramori, G., Pandit, A. & Papi, A. Is there a difference between chronic airway inflammation in chronic severe asthma and chronic obstructive pulmonary disease? Curr. Opin. Allergy Clin. Immunol. 5, 77-83 (2005).
90. Nathan, C. Neutrophils and immunity: challenges and opportunities. Nature Rev. Immunol. 6, 173-82 (2006).
91. Ley, K., Smith, E. & Stark, M. A. IL-17A-producing neutrophil-regulatory Tn lymphocytes. Immunol. Res. 34, 229-242 (2006).
92. Chatham, W. W. et al. Degradation of human articular cartilage by neutrophils in synovial fluid. Arthritis Rheum. 36, 51-58 (1993).
93. Mohr, W., Kohler, G. & Wessinghage, D. Polymorphonuclear granulocytes in rheumatic tissue destruction. II. Demonstration of PMNs in rheumatoid nodules by electron microscopy. Rheumatol. Int. 1, 21-28 (1981).
94. Mohr, W., Pelster, B. & Wessinghage, D. Polymorphonuclear granulocytes in rheumatic tissue destruction. VI. The occurrence of PMNs in menisci of patients with rheumatoid arthritis. Rheumatol. Int. 5, 39-44 (1984).
95. Mohr, W., Westerhellweg, H. & Wessinghage, D. Polymorphonuclear granulocytes in rheumatic tissue destruction. III. An electron microscopic study of PMNs at the pannus-cartilage junction in rheumatoid arthritis. Ann. Rheum. Dis. 40, 396-399 (1981).
96. Mohr, W., Wild, A. & Wolf, H. P. Role of polymorphs in inflammatory cartilage destruction in adjuvant arthritis of rats. Ann. Rheum. Dis. 40, 171-176 (1981).
97. Nandakumar, K. S., Svensson, L. & Holmdahl, R. Collagen type II-specific monoclonal antibody-induced arthritis in mice: description of the disease and the influence of age, sex, and genes. Am. J. Pathol. 163, 1827-1837 (2003).
98. Capsoni, F. et al. Effect of adalimumab on neutrophil function in patients with rheumatoid arthritis. Arthritis Res. Ther. 7, R250-R255 (2005).
99. Schramm, R. & Thorlacius, H. Neutrophil recruitment in mast cell-dependent inflammation: inhibitory mechanisms of glucocorticoids. Inflamm. Res. 53, 644-652 (2004).
100. Puri, K. D. et al. The role of endothelial PI3Kγ activity in neutrophil trafficking. Blood 106, 150-157 (2005).
101. Puri, K. D. et al. Mechanisms and implications of phosphoinositide 3-kinase δ in promoting neutrophil trafficking into inflamed tissue. Blood 103, 3448-3456 (2004). References 100 and 101 indicate cooperativity between PI3Kδ and PI3Kγ in neutrophil extravasation.
102. Condliffe, A. M. 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 106, 1432-1440 (2005). Describes the cooperativity between PI3Kδ and PI3Kγ in ROS production by neutrophils.
103. Frey, R. S. et al. Phosphatidylinositol 3-kinase γ signaling through protein kinase Cζ induces NADPH oxidase-mediated oxidant generation and NF-κB activation in endothelial cells. J. Biol. Chem. 281, 16128-16138 (2006).
104. Rossi, A. G. et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nature Med. 12, 1056-1064 (2006).
105. Okayama, Y. & Kawakami, T. Development, migration, and survival of mast cells. Immunol. Res. 34, 97-115 (2006).
106. Theoharides, T. C. & Cochrane, D. E. Critical role of mast cells in inflammatory diseases and the effect of acute stress. J. Neuroimmunol. 146, 1-12 (2004).
107. Olsson, N., Ulfgren, A. K. & Nilsson, G. Demonstration of mast cell chemotactic activity in synovial fluid from rheumatoid patients. Ann. Rheum. Dis. 60, 187-193 (2001).
108. Galli, S. J., Nakae, S. & Tsai, M. Mast cells in the development of adaptive immune responses. Nature Immunol. 6, 135-142 (2005).
109. Yano, H. et al. Inhibition of histamine secretion by wortmannin through the blockade of phosphatidylinositol 3-kinase in RBL-2H3 cells. J. Biol. Chem. 268, 25846-25856 (1993).
110. Melendez, A. J., Gillooly, D. J., Harnett, M. M. & Allen, J. M. Aggregation of the human high affinity immunoglobulin G receptor (FcγRI) activates both tyrosine kinase and G protein-coupled phosphoinositide 3-kinase isoforms. Proc. Natl Acad. Sci. USA 95, 2169-2174 (1998).
111. Hammaker, D., Sweeney, S. & Firestein, G. S. Signal transduction networks in rheumatoid arthritis. Ann. Rheum. Dis. 62 (Suppl. 2), 86-89 (2003).
112. Szekanecz, Z., Szucs, G., Szanto, S. & Koch, A. E. Chemokines in rheumatic diseases. Curr. Drug Targets 7, 91-102 (2006).
113. Mackay, C. R. Chemokines: immunology's high impact factors. Nature Immunol. 2, 95-101 (2001).
114. Hemmer, B., Archelos, J. J. & Hartung, H. P. New concepts in the immunopathogenesis of multiple sclerosis. Nature Rev. Neurosci. 3, 291-301 (2002).
115. Sospedra, M. & Martin, R. Immunology of multiple sclerosis. Annu. Rev. Immunol. 23, 683-747 (2005).
116. Busse, W. W. & Lemanske, R. F. Jr. Asthma. N. Engl. J. Med. 344, 350-362 (2001).
117. Wymann, M. P. & Marone, R. Phosphoinositide 3-kinase in disease: timing, location, and scaffolding. Curr. Opin. Cell Biol. 17, 141-149 (2005).
118. Stoyanov, B. et al. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science 269, 690-693 (1995).
119. Suire, S. et al. Gβγs and the Ras binding domain of p110γ are both important regulators of PI3Kγ signalling in neutrophils. Nature Cell Biol. 8, 1303-1309 (2006).
120. Lambeth, J. D. NOX enzymes and the biology of reactive oxygen. Nature Rev. Immunol. 4, 181-189 (2004).
121. Kanai, F. et al. The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nature Cell Biol. 3, 675-678 (2001). Reports a direct link between PI3K and the Phox complex.
122. Perisic, O. et al. The role of phosphoinositides and phosphorylation in regulation of NADPH oxidase. Adv. Enzyme Regul. 44, 279-298 (2004).
123. 2, PtdIns(3)P, and PKCδ in intracellular production of reactive oxygen species by the NADPH oxidase. Mol. Cell 11, 35-47 (2003).
124. Rhee, S. G. et al. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr. Opin. Cell Biol. 17, 183-189 (2005).
125. Gilfillan, A. M. & Tkaczyk, C. Integrated signalling pathways for mast-cell activation. Nature Rev. Immunol. 6, 218-230 (2006).
126. Wymann, M. P. et al. Phosphoinositide 3-kinase γ: a key modulator in inflammation and allergy. Biochem. Soc. Trans. 31, 275-280 (2003). Describes the concept of cooperativity between PI3Kδ and PI3Kγ in mast-cell signalling and function.
127. Hirsch, E. et al. Signaling through PI3Kγ: a common platform for leukocyte, platelet and cardiovascular stress sensing. Thromb. Haemost. 95, 29-35 (2006).
128. Tkaczyk, C., Beaven, M. A., Brachman, S. M., Metcalfe, D. D. & Gilfillan, A. M. The phospholipase Cγ1-dependent pathway of FcεRI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase. J. Biol. Chem. 278, 48474-48484 (2003).