PDBsum entry 2a5u

Go to PDB code: 
protein ligands links
Transferase PDB id
Protein chain
839 a.a. *
Waters ×20
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of human pi3kgamma complexed with as605240
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, gamma isoform. Chain: a. Fragment: p110 subunit gamma, residues 143-1101. Synonym: phosphatidylinositol 3-kinase catalytic subunit, pi3-kinase p110 subunit gamma, ptdins- 3-kinase p110, pi3k, pi3kgamma. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: sf9. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
2.70Å     R-factor:   0.285     R-free:   0.351
Authors: M.Camps,T.Ruckle,H.Ji,V.Ardissone,F.Rintelen,J.Shaw, C.Ferrandi,C.Chabert,C.Gillieron,B.Francon,T.Martin, D.Gretener,D.Perrin,D.Leroy,P.-A.Vitte,E.Hirsch,M.P.Wymann, R.Cirillo,M.K.Schwarz,C.Rommel
Key ref:
M.Camps et al. (2005). Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med, 11, 936-943. PubMed id: 16127437 DOI: 10.1038/nm1284
01-Jul-05     Release date:   20-Sep-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P48736  (PK3CG_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
1102 a.a.
839 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.  - Phosphatidylinositol-4,5-bisphosphate 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

1-Phosphatidyl-myo-inositol Metabolism
      Reaction: ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
+ 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
+ 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
   Enzyme class 3: E.C.  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ phosphoprotein
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     phosphatidylinositol-mediated signaling   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     2 terms  


DOI no: 10.1038/nm1284 Nat Med 11:936-943 (2005)
PubMed id: 16127437  
Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.
M.Camps, T.Rückle, H.Ji, V.Ardissone, F.Rintelen, J.Shaw, C.Ferrandi, C.Chabert, C.Gillieron, B.Françon, T.Martin, D.Gretener, D.Perrin, D.Leroy, P.A.Vitte, E.Hirsch, M.P.Wymann, R.Cirillo, M.K.Schwarz, C.Rommel.
Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.
  Selected figure(s)  
Figure 3.
Figure 3. Effects of PI3K gamma inhibitors on in vitro and in vivo chemotaxis.
Figure 4.
Figure 4. Elimination of PI3K gamma function largely protects against CII-IA. (a) Mean paw thickness in Pik3cg-/- and Pik3cg+/+ mice after CII-IA induction. Data (n 5) are representative of two independent experiments. (b) H&E (synovial inflammation, original magnification, 50; neutrophils, original magnification, 1,000) - or safranin O (cartilage erosion, original magnification, 100) -stained representative joint sections from experiment shown in a, and sham-treated Pik3cg+/+ mice. Arrowheads indicate areas shown at higher magnification in the neutrophil column. Arrows point to neutrophils. (c) Histological scores of inflammation and cartilage erosion from the experiment shown in a. (d) Neutrophil infiltration in joint sections from experiment shown in a. Data are expressed as percentage of neutrophils from total number of cells. (e) CII-IA development represented as mean paw thickness in Pik3cg+/+ mice treated with vehicle or AS-605240 (n 5). Double arrow indicates initiation of the treatment. (f) H&E (original magnification, 50) - and safranin O (original magnification, 100) -stained representative joint sections from experiment shown in e. (g) Histological scores of synovial inflammation and cartilage erosion from the experiment shown in e. Data are mean s.e.m. * P < 0.05, ** P < 0.01, *** P < 0.001. Dotted line indicates mean paw thickness level in healthy animals.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Med (2005, 11, 936-943) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20626398 A.Eisenreich, and U.Rauch (2011).
PI3K inhibitors in cardiovascular disease.
  Cardiovasc Ther, 29, 29-36.  
21306579 G.Volpi, F.Facchinetti, N.Moretto, M.Civelli, and R.Patacchini (2011).
Cigarette smoke and α,β-unsaturated aldehydes elicit VEGF release through the p38 MAPK pathway in human airway smooth muscle cells and lung fibroblasts.
  Br J Pharmacol, 163, 649-661.  
21360822 J.A.Pinson, O.Schmidt-Kittler, J.Zhu, I.G.Jennings, K.W.Kinzler, B.Vogelstein, D.K.Chalmers, and P.E.Thompson (2011).
Thiazolidinedione-Based PI3Kα Inhibitors: An Analysis of Biochemical and Virtual Screening Methods.
  ChemMedChem, 6, 514-522.  
20818438 J.Dwyer, A.Le Guelte, E.M.Galan Moya, M.Sumbal, A.Carlotti, L.Douguet, J.S.Gutkind, P.A.Grange, N.Dupin, and J.Gavard (2011).
Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor.
  Oncogene, 30, 190-200.  
21287545 L.Berod, C.Heinemann, S.Heink, A.Escher, C.Stadelmann, S.Drube, R.Wetzker, J.Norgauer, and T.Kamradt (2011).
PI3Kγ deficiency delays the onset of experimental autoimmune encephalomyelitis and ameliorates its clinical outcome.
  Eur J Immunol, 41, 833-844.  
21035483 L.Stephens, and P.Hawkins (2011).
Signalling via class IA PI3Ks.
  Adv Enzyme Regul, 51, 27-36.  
21250979 M.C.Olianas, S.Dedoni, and P.Onali (2011).
δ-Opioid receptors stimulate GLUT1-mediated glucose uptake through Src- and IGF-1 receptor-dependent activation of PI3-kinase signalling in CHO cells.
  Br J Pharmacol, 163, 624-637.  
21436039 N.Kobayashi, K.Ueki, Y.Okazaki, A.Iwane, N.Kubota, M.Ohsugi, M.Awazawa, M.Kobayashi, T.Sasako, K.Kaneko, M.Suzuki, Y.Nishikawa, K.Hara, K.Yoshimura, I.Koshima, S.Goyama, K.Murakami, J.Sasaki, R.Nagai, M.Kurokawa, T.Sasaki, and T.Kadowaki (2011).
Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance.
  Proc Natl Acad Sci U S A, 108, 5753-5758.  
21244371 R.C.Dutra, M.Cola, D.F.Leite, A.F.Bento, R.F.Claudino, A.F.Nascimento, P.C.Leal, and J.B.Calixto (2011).
Inhibitor of PI3Kγ ameliorates TNBS-induced colitis in mice by affecting the functional activity of CD4+CD25+FoxP3+ regulatory T cells.
  Br J Pharmacol, 163, 358-374.  
20081827 A.Berndt, S.Miller, O.Williams, D.D.Le, B.T.Houseman, J.I.Pacold, F.Gorrec, W.C.Hon, Y.Liu, C.Rommel, P.Gaillard, T.Rückle, M.K.Schwarz, K.M.Shokat, J.P.Shaw, and R.L.Williams (2010).
The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
  Nat Chem Biol, 6, 117-124.
PDB codes: 2wxe 2wxf 2wxg 2wxh 2wxi 2wxj 2wxk 2wxl 2wxm 2wxn 2wxo 2wxp 2wxq 2wxr 2x38
20162662 A.Ghigo, F.Damilano, L.Braccini, and E.Hirsch (2010).
PI3K inhibition in inflammation: Toward tailored therapies for specific diseases.
  Bioessays, 32, 185-196.  
19907415 A.Schreiber, S.Rolle, L.Peripelittchenko, J.Rademann, W.Schneider, F.C.Luft, and R.Kettritz (2010).
Phosphoinositol 3-kinase-gamma mediates antineutrophil cytoplasmic autoantibody-induced glomerulonephritis.
  Kidney Int, 77, 118-128.  
20824797 C.Bocelli-Tyndall, P.Zajac, N.Di Maggio, E.Trella, F.Benvenuto, G.Iezzi, A.Scherberich, A.Barbero, S.Schaeren, V.Pistoia, G.Spagnoli, M.Vukcevic, I.Martin, and A.Tyndall (2010).
Fibroblast growth factor 2 and platelet-derived growth factor, but not platelet lysate, induce proliferation-dependent, functional class II major histocompatibility complex antigen in human mesenchymal stem cells.
  Arthritis Rheum, 62, 3815-3825.  
19910414 D.R.Bridge, M.J.Novotny, E.R.Moore, and J.C.Olson (2010).
Role of host cell polarity and leading edge properties in Pseudomonas type III secretion.
  Microbiology, 156, 356-373.  
  20971740 Launay, J.Vreijling, L.M.Hartkamp, O.N.Karpus, J.R.Abreu, M.A.van Maanen, M.E.Sanders, A.M.Grabiec, J.Hamann, H.Ørum, M.J.Vervoordeldonk, K.Fluiter, P.P.Tak, and K.A.Reedquist (2010).
Silencing the expression of Ras family GTPase homologues decreases inflammation and joint destruction in experimental arthritis.
  Am J Pathol, 177, 3010-3024.  
20132480 E.A.Corey, Y.Bobkov, A.Pezier, and B.W.Ache (2010).
Phosphoinositide 3-kinase mediated signaling in lobster olfactory receptor neurons.
  J Neurochem, 113, 341-350.  
20025958 G.F.Passos, C.P.Figueiredo, R.D.Prediger, K.A.Silva, J.M.Siqueira, F.S.Duarte, P.C.Leal, R.Medeiros, and J.B.Calixto (2010).
Involvement of phosphoinositide 3-kinase gamma in the neuro-inflammatory response and cognitive impairments induced by beta-amyloid 1-40 peptide in mice.
  Brain Behav Immun, 24, 493-501.  
20616072 H.Kang, W.Chang, M.Hurley, A.Vignery, and D.Wu (2010).
Important roles of PI3Kgamma in osteoclastogenesis and bone homeostasis.
  Proc Natl Acad Sci U S A, 107, 12901-12906.  
20338884 H.L.Wright, R.J.Moots, R.C.Bucknall, and S.W.Edwards (2010).
Neutrophil function in inflammation and inflammatory diseases.
  Rheumatology (Oxford), 49, 1618-1631.  
20167705 H.Mueller, A.Stadtmann, H.Van Aken, E.Hirsch, D.Wang, K.Ley, and A.Zarbock (2010).
Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) gamma2 and PI3Kgamma pathways.
  Blood, 115, 3118-3127.  
19797129 J.Reutershan, M.S.Saprito, D.Wu, T.Rückle, and K.Ley (2010).
Phosphoinositide 3-kinase gamma required for lipopolysaccharide-induced transepithelial neutrophil trafficking in the lung.
  Eur Respir J, 35, 1137-1147.  
20351305 K.Maeda, H.Mehta, D.A.Drevets, and K.M.Coggeshall (2010).
IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production.
  Blood, 115, 4699-4706.  
  20032232 K.Ukhanov, E.A.Corey, D.Brunert, K.Klasen, and B.W.Ache (2010).
Inhibitory odorant signaling in Mammalian olfactory receptor neurons.
  J Neurophysiol, 103, 1114-1122.  
20374644 M.Gruen, C.Rose, C.König, M.Gajda, R.Wetzker, and R.Bräuer (2010).
Loss of phosphoinositide 3-kinase gamma decreases migration and activation of phagocytes but not T cell activation in antigen-induced arthritis.
  BMC Musculoskelet Disord, 11, 63.  
20056919 M.Siragusa, R.Katare, M.Meloni, F.Damilano, E.Hirsch, C.Emanueli, and P.Madeddu (2010).
Involvement of phosphoinositide 3-kinase gamma in angiogenesis and healing of experimental myocardial infarction in mice.
  Circ Res, 106, 757-768.  
20189103 O.Williams, B.T.Houseman, E.J.Kunkel, B.Aizenstein, R.Hoffman, Z.A.Knight, and K.M.Shokat (2010).
Discovery of dual inhibitors of the immune cell PI3Ks p110delta and p110gamma: a prototype for new anti-inflammatory drugs.
  Chem Biol, 17, 123-134.  
19962457 S.B.Gabelli, D.Mandelker, O.Schmidt-Kittler, B.Vogelstein, and L.M.Amzel (2010).
Somatic mutations in PI3Kalpha: structural basis for enzyme activation and drug design.
  Biochim Biophys Acta, 1804, 533-540.  
20159593 S.K.Yoo, Q.Deng, P.J.Cavnar, Y.I.Wu, K.M.Hahn, and A.Huttenlocher (2010).
Differential regulation of protrusion and polarity by PI3K during neutrophil motility in live zebrafish.
  Dev Cell, 18, 226-236.  
20526370 S.McNulty, W.Bornmann, J.Schriewer, C.Werner, S.K.Smith, V.A.Olson, I.K.Damon, R.M.Buller, J.Heuser, and D.Kalman (2010).
Multiple phosphatidylinositol 3-kinases regulate vaccinia virus morphogenesis.
  PLoS One, 5, e10884.  
20482767 S.Toyama, N.Tamura, K.Haruta, T.Karakida, S.Mori, T.Watanabe, T.Yamori, and Y.Takasaki (2010).
Inhibitory effects of ZSTK474, a novel phosphoinositide 3-kinase inhibitor, on osteoclasts and collagen-induced arthritis in mice.
  Arthritis Res Ther, 12, R92.  
20510239 T.M.Lindstrom, and W.H.Robinson (2010).
A multitude of kinases--which are the best targets in treating rheumatoid arthritis?
  Rheum Dis Clin North Am, 36, 367-383.  
20721532 V.Fanelli, V.Puntorieri, B.Assenzio, E.L.Martin, V.Elia, M.Bosco, L.Delsedime, L.Del Sorbo, A.Ferrari, S.Italiano, A.Ghigo, A.S.Slutsky, E.Hirsch, and V.M.Ranieri (2010).
Pulmonary-derived phosphoinositide 3-kinase gamma (PI3Kγ) contributes to ventilator-induced lung injury and edema.
  Intensive Care Med, 36, 1935-1945.  
20093365 V.May, E.Lutz, C.MacKenzie, K.C.Schutz, K.Dozark, and K.M.Braas (2010).
Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase gamma and vesicle endocytosis for neuronal survival.
  J Biol Chem, 285, 9749-9761.  
20201075 V.R.Konda, A.Desai, G.Darland, J.S.Bland, and M.L.Tripp (2010).
META060 inhibits osteoclastogenesis and matrix metalloproteinases in vitro and reduces bone and cartilage degradation in a mouse model of rheumatoid arthritis.
  Arthritis Rheum, 62, 1683-1692.  
20224967 V.Spitzenberg, C.König, S.Ulm, R.Marone, L.Röpke, J.P.Müller, M.Grün, R.Bauer, I.Rubio, M.P.Wymann, A.Voigt, and R.Wetzker (2010).
Targeting PI3K in neuroblastoma.
  J Cancer Res Clin Oncol, 136, 1881-1890.  
19622728 A.Di Lorenzo, C.Fernández-Hernando, G.Cirino, and W.C.Sessa (2009).
Akt1 is critical for acute inflammation and histamine-mediated vascular leakage.
  Proc Natl Acad Sci U S A, 106, 14552-14557.  
19906996 B.Kurig, A.Shymanets, T.Bohnacker, Prajwal, C.Brock, M.R.Ahmadian, M.Schaefer, A.Gohla, C.Harteneck, M.P.Wymann, E.Jeanclos, and B.Nürnberg (2009).
Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110gamma.
  Proc Natl Acad Sci U S A, 106, 20312-20317.  
19137016 C.Guo, A.V.Gasparian, Z.Zhuang, D.A.Bosykh, A.A.Komar, A.V.Gudkov, and K.V.Gurova (2009).
9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-kappaB and p53 pathways.
  Oncogene, 28, 1151-1161.  
19028980 D.H.Lim, J.Y.Cho, D.J.Song, S.Y.Lee, M.Miller, and D.H.Broide (2009).
PI3K gamma-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling.
  Am J Physiol Lung Cell Mol Physiol, 296, L210-L219.  
19182393 D.Kong, S.Yaguchi, and T.Yamori (2009).
Effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor, on DNA-dependent protein kinase.
  Biol Pharm Bull, 32, 297-300.  
19376709 E.Hirsch, L.Braccini, E.Ciraolo, F.Morello, and A.Perino (2009).
Twice upon a time: PI3K's secret double life exposed.
  Trends Biochem Sci, 34, 244-248.  
19038971 F.Morello, A.Perino, and E.Hirsch (2009).
Phosphoinositide 3-kinase signalling in the vascular system.
  Cardiovasc Res, 82, 261-271.  
19549714 G.M.Pigeau, J.Kolic, B.J.Ball, M.B.Hoppa, Y.W.Wang, T.Rückle, M.Woo, J.E.Manning Fox, and P.E.MacDonald (2009).
Insulin granule recruitment and exocytosis is dependent on p110gamma in insulinoma and human beta-cells.
  Diabetes, 58, 2084-2092.  
19248109 G.Palmer, D.Talabot-Ayer, C.Lamacchia, D.Toy, C.A.Seemayer, S.Viatte, A.Finckh, D.E.Smith, and C.Gabay (2009).
Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis.
  Arthritis Rheum, 60, 738-749.  
19255141 J.Gavard, X.Hou, Y.Qu, A.Masedunskas, D.Martin, R.Weigert, X.Li, and J.S.Gutkind (2009).
A role for a CXCR2/phosphatidylinositol 3-kinase gamma signaling axis in acute and chronic vascular permeability.
  Mol Cell Biol, 29, 2469-2480.  
19232066 J.M.Waldburger, and G.S.Firestein (2009).
Garden of therapeutic delights: new targets in rheumatic diseases.
  Arthritis Res Ther, 11, 206.  
19139077 L.M.Sly, M.J.Hamilton, E.Kuroda, V.W.Ho, F.L.Antignano, S.L.Omeis, C.J.van Netten-Thomas, D.Wong, H.K.Brugger, O.Williams, M.E.Feldman, B.T.Houseman, D.Fiedler, K.M.Shokat, and G.Krystal (2009).
SHIP prevents lipopolysaccharide from triggering an antiviral response in mice.
  Blood, 113, 2945-2954.  
19384329 L.Pallan, C.O.Savage, and L.Harper (2009).
ANCA-associated vasculitis: from bench research to novel treatments.
  Nat Rev Nephrol, 5, 278-286.  
19644878 L.Stangenberg, C.Ellson, V.Cortez-Retamozo, A.Ortiz-Lopez, H.Yuan, J.Blois, R.A.Smith, M.B.Yaffe, R.Weissleder, C.Benoist, D.Mathis, L.Josephson, and U.Mahmood (2009).
Abrogation of antibody-induced arthritis in mice by a self-activating viridin prodrug and association with impaired neutrophil and endothelial cell function.
  Arthritis Rheum, 60, 2314-2324.  
19298527 M.Baran, L.N.Möllers, S.Andersson, I.M.Jonsson, A.K.Ekwall, J.Bjersing, A.Tarkowski, and M.Bokarewa (2009).
Survivin is an essential mediator of arthritis interacting with urokinase signalling.
  J Cell Mol Med, 13, 3797-3808.  
19483102 M.Holinstat, A.M.Preininger, S.B.Milne, W.J.Hudson, H.A.Brown, and H.E.Hamm (2009).
Irreversible platelet activation requires protease-activated receptor 1-mediated signaling to phosphatidylinositol phosphates.
  Mol Pharmacol, 76, 301-313.  
19772834 M.Mavers, E.M.Ruderman, and H.Perlman (2009).
Intracellular signal pathways: potential for therapies.
  Curr Rheumatol Rep, 11, 378-385.  
19454011 N.Butoescu, C.A.Seemayer, G.Palmer, P.A.Guerne, C.Gabay, E.Doelker, and O.Jordan (2009).
Magnetically retainable microparticles for drug delivery to the joint: efficacy studies in an antigen-induced arthritis model in mice.
  Arthritis Res Ther, 11, R72.  
19620252 R.Cheung, M.Malik, V.Ravyn, B.Tomkowicz, A.Ptasznik, and R.G.Collman (2009).
An arrestin-dependent multi-kinase signaling complex mediates MIP-1beta/CCL4 signaling and chemotaxis of primary human macrophages.
  J Leukoc Biol, 86, 833-845.  
19233845 R.P.Gobert, M.van den Eijnden, C.Szyndralewiez, C.Jorand-Lebrun, D.Swinnen, L.Chen, C.Gillieron, F.Pixley, P.Juillard, P.Gerber, C.Johnson-Léger, S.Halazy, M.Camps, A.Bombrun, M.Shipp, P.A.Vitte, V.Ardissone, C.Ferrandi, D.Perrin, C.Rommel, and R.H.van Huijsduijnen (2009).
GLEPP1/Protein-tyrosine Phosphatase {phi} Inhibitors Block Chemotaxis in Vitro and in Vivo and Improve Murine Ulcerative Colitis.
  J Biol Chem, 284, 11385-11395.  
  19349365 S.André, D.F.Tough, S.Lacroix-Desmazes, S.V.Kaveri, and J.Bayry (2009).
Surveillance of antigen-presenting cells by CD4+ CD25+ regulatory T cells in autoimmunity: immunopathogenesis and therapeutic implications.
  Am J Pathol, 174, 1575-1587.  
19168509 S.Heymans, E.Hirsch, S.D.Anker, P.Aukrust, J.L.Balligand, J.W.Cohen-Tervaert, H.Drexler, G.Filippatos, S.B.Felix, L.Gullestad, D.Hilfiker-Kleiner, S.Janssens, R.Latini, G.Neubauer, W.J.Paulus, B.Pieske, P.Ponikowski, B.Schroen, H.P.Schultheiss, C.Tschöpe, M.Van Bilsen, F.Zannad, J.McMurray, and A.M.Shah (2009).
Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology.
  Eur J Heart Fail, 11, 119-129.  
19700402 S.Kim, P.Mangin, C.Dangelmaier, R.Lillian, S.P.Jackson, J.L.Daniel, and S.P.Kunapuli (2009).
Role of phosphoinositide 3-kinase beta in glycoprotein VI-mediated Akt activation in platelets.
  J Biol Chem, 284, 33763-33772.  
19794881 S.Taouji, S.Dahan, R.Bossé, and E.Chevet (2009).
Current Screens Based on the AlphaScreen Technology for Deciphering Cell Signalling Pathways.
  Curr Genomics, 10, 93.  
19225663 T.J.Sundstrom, A.C.Anderson, and D.L.Wright (2009).
Inhibitors of phosphoinositide-3-kinase: a structure-based approach to understanding potency and selectivity.
  Org Biomol Chem, 7, 840-850.  
19580826 T.Sasaki, S.Takasuga, J.Sasaki, S.Kofuji, S.Eguchi, M.Yamazaki, and A.Suzuki (2009).
Mammalian phosphoinositide kinases and phosphatases.
  Prog Lipid Res, 48, 307-343.  
18383341 Oliveira, E.Candelario-Jalil, H.S.Bhatia, K.Lieb, M.Hüll, and B.L.Fiebich (2008).
Regulation of prostaglandin E2 synthase expression in activated primary rat microglia: evidence for uncoupled regulation of mPGES-1 and COX-2.
  Glia, 56, 844-855.  
17998941 A.Denley, S.Kang, U.Karst, and P.K.Vogt (2008).
Oncogenic signaling of class I PI3K isoforms.
  Oncogene, 27, 2561-2574.  
18779195 A.S.Cowburn, A.M.Condliffe, N.Farahi, C.Summers, and E.R.Chilvers (2008).
Advances in neutrophil biology: clinical implications.
  Chest, 134, 606-612.  
18488142 A.V.Smrcka (2008).
G protein betagamma subunits: central mediators of G protein-coupled receptor signaling.
  Cell Mol Life Sci, 65, 2191-2214.  
18537559 A.V.Smrcka, D.M.Lehmann, and A.L.Dessal (2008).
G protein betagamma subunits as targets for small molecule therapeutic development.
  Comb Chem High Throughput Screen, 11, 382-395.  
17883327 A.Viola, and A.D.Luster (2008).
Chemokines and their receptors: drug targets in immunity and inflammation.
  Annu Rev Pharmacol Toxicol, 48, 171-197.  
18227218 C.Guiducci, C.Ghirelli, M.A.Marloie-Provost, T.Matray, R.L.Coffman, Y.J.Liu, F.J.Barrat, and V.Soumelis (2008).
PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation.
  J Exp Med, 205, 315-322.  
18711436 C.R.Mackay (2008).
Moving targets: cell migration inhibitors as new anti-inflammatory therapies.
  Nat Immunol, 9, 988-998.  
18006643 D.M.Lehmann, A.M.Seneviratne, and A.V.Smrcka (2008).
Small molecule disruption of G protein beta gamma subunit signaling inhibits neutrophil chemotaxis and inflammation.
  Mol Pharmacol, 73, 410-418.  
18420279 E.Hirsch, E.Ciraolo, A.Ghigo, and C.Costa (2008).
Taming the PI3K team to hold inflammation and cancer at bay.
  Pharmacol Ther, 118, 192-205.  
18602341 F.Pinheiro da Silva, M.Aloulou, M.Benhamou, and R.C.Monteiro (2008).
Inhibitory ITAMs: a matter of life and death.
  Trends Immunol, 29, 366-373.  
18332138 G.J.Litherland, C.Dixon, R.L.Lakey, T.Robson, D.Jones, D.A.Young, T.E.Cawston, and A.D.Rowan (2008).
Synergistic collagenase expression and cartilage collagenolysis are phosphatidylinositol 3-kinase/Akt signaling-dependent.
  J Biol Chem, 283, 14221-14229.  
18046317 H.Kuwana, Y.Terada, T.Kobayashi, T.Okado, J.M.Penninger, J.Irie-Sasaki, T.Sasaki, and S.Sasaki (2008).
The phosphoinositide-3 kinase gamma-Akt pathway mediates renal tubular injury in cisplatin nephrotoxicity.
  Kidney Int, 73, 430-445.  
18085662 H.Ohno, Y.Uemura, H.Murooka, H.Takanashi, T.Tokieda, Y.Ohzeki, K.Kubo, and I.Serizawa (2008).
The orally-active and selective c-Fms tyrosine kinase inhibitor Ki20227 inhibits disease progression in a collagen-induced arthritis mouse model.
  Eur J Immunol, 38, 283-291.  
18658026 J.Barbi, H.E.Cummings, B.Lu, S.Oghumu, T.Rückle, C.Rommel, W.Lafuse, C.C.Whitacre, and A.R.Satoskar (2008).
PI3Kgamma (PI3Kgamma) is essential for efficient induction of CXCR3 on activated T cells.
  Blood, 112, 3048-3051.  
18544649 J.Guillermet-Guibert, K.Bjorklof, A.Salpekar, C.Gonella, F.Ramadani, A.Bilancio, S.Meek, A.J.Smith, K.Okkenhaug, and B.Vanhaesebroeck (2008).
The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma.
  Proc Natl Acad Sci U S A, 105, 8292-8297.  
18662984 J.Sai, D.Raman, Y.Liu, J.Wikswo, and A.Richmond (2008).
Parallel phosphatidylinositol 3-kinase (PI3K)-dependent and Src-dependent pathways lead to CXCL8-mediated Rac2 activation and chemotaxis.
  J Biol Chem, 283, 26538-26547.  
18300054 J.Won, and G.H.Lee (2008).
T-cell-targeted signaling inhibitors.
  Int Rev Immunol, 27, 19-41.  
  18250464 K.Ali, M.Camps, W.P.Pearce, H.Ji, T.Rückle, N.Kuehn, C.Pasquali, C.Chabert, C.Rommel, and B.Vanhaesebroeck (2008).
Isoform-Specific Functions of Phosphoinositide 3-Kinases: p110{delta} but Not p110{gamma} Promotes Optimal Allergic Responses In Vivo.
  J Immunol, 180, 2538-2544.  
18388186 L.N.Jackson, S.D.Larson, S.R.Silva, P.G.Rychahou, L.A.Chen, S.Qiu, S.Rajaraman, and B.M.Evers (2008).
PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy.
  Am J Physiol Gastrointest Liver Physiol, 294, G1401-G1410.  
19029450 L.Zitvogel, and G.Kroemer (2008).
The dilemma of anticancer therapy: tumor-specific versus immune effects.
  Blood, 112, 4364-4365.  
18489260 M.Frazzetto, C.Suphioglu, J.Zhu, O.Schmidt-Kittler, I.G.Jennings, S.L.Cranmer, S.P.Jackson, K.W.Kinzler, B.Vogelstein, and P.E.Thompson (2008).
Dissecting isoform selectivity of PI3K inhibitors: the role of non-conserved residues in the catalytic pocket.
  Biochem J, 414, 383-390.  
18216772 M.P.Wymann, and R.Schneiter (2008).
Lipid signalling in disease.
  Nat Rev Mol Cell Biol, 9, 162-176.  
18523230 M.S.Thomas, J.S.Mitchell, C.C.DeNucci, A.L.Martin, and Y.Shimizu (2008).
The p110gamma isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites.
  J Leukoc Biol, 84, 814-823.  
18711433 P.Friedl, and B.Weigelin (2008).
Interstitial leukocyte migration and immune function.
  Nat Immunol, 9, 960-969.  
18820032 Q.Lai Kwan Lam, O.King Hung Ko, B.J.Zheng, and L.Lu (2008).
Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis.
  Proc Natl Acad Sci U S A, 105, 14993-14998.  
  18453587 R.Cheung, V.Ravyn, L.Wang, A.Ptasznik, and R.G.Collman (2008).
Signaling mechanism of HIV-1 gp120 and virion-induced IL-1beta release in primary human macrophages.
  J Immunol, 180, 6675-6684.  
19568798 R.M.Gunn, and H.C.Hailes (2008).
Insights into the PI3-K-PKB-mTOR signalling pathway from small molecules.
  J Chem Biol, 1, 49-62.  
18596232 S.Chen, F.Lin, M.E.Shin, F.Wang, L.Shen, and H.E.Hamm (2008).
RACK1 regulates directional cell migration by acting on G betagamma at the interface with its effectors PLC beta and PI3K gamma.
  Mol Biol Cell, 19, 3909-3922.  
18509048 S.Sauer, L.Bruno, A.Hertweck, D.Finlay, M.Leleu, M.Spivakov, Z.A.Knight, B.S.Cobb, D.Cantrell, E.O'Connor, K.M.Shokat, A.G.Fisher, and M.Merkenschlager (2008).
T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR.
  Proc Natl Acad Sci U S A, 105, 7797-7802.  
18412166 T.M.Randis, K.D.Puri, H.Zhou, and T.G.Diacovo (2008).
Role of PI3Kdelta and PI3Kgamma in inflammatory arthritis and tissue localization of neutrophils.
  Eur J Immunol, 38, 1215-1224.  
18587386 Y.Aikawa, K.Morimoto, T.Yamamoto, H.Chaki, A.Hashiramoto, H.Narita, S.Hirono, and S.Shiozawa (2008).
Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1.
  Nat Biotechnol, 26, 817-823.  
19384426 A.Arcaro, and A.S.Guerreiro (2007).
The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications.
  Curr Genomics, 8, 271-306.  
17501698 A.F.Hezel, and D.P.Ryan (2007).
Emerging therapies for colorectal cancer.
  Expert Opin Investig Drugs, 16, 867-876.  
17502453 C.J.Ong, A.Ming-Lum, M.Nodwell, A.Ghanipour, L.Yang, D.E.Williams, J.Kim, L.Demirjian, P.Qasimi, J.Ruschmann, L.P.Cao, K.Ma, S.W.Chung, V.Duronio, R.J.Andersen, G.Krystal, and A.L.Mui (2007).
Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells.
  Blood, 110, 1942-1949.  
17290298 C.Rommel, M.Camps, and H.Ji (2007).
PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond?
  Nat Rev Immunol, 7, 191-201.  
17614878 D.A.Medina-Tato, S.G.Ward, and M.L.Watson (2007).
Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond.
  Immunology, 121, 448-461.  
17711503 D.Kong, and T.Yamori (2007).
ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms.
  Cancer Sci, 98, 1638-1642.  
17626838 H.Ji, F.Rintelen, C.Waltzinger, D.Bertschy Meier, A.Bilancio, W.Pearce, E.Hirsch, M.P.Wymann, T.Rückle, M.Camps, B.Vanhaesebroeck, K.Okkenhaug, and C.Rommel (2007).
Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation.
  Blood, 110, 2940-2947.  
17723215 I.Tassi, M.Cella, S.Gilfillan, I.Turnbull, T.G.Diacovo, J.M.Penninger, and M.Colonna (2007).
p110gamma and p110delta phosphoinositide 3-kinase signaling pathways synergize to control development and functions of murine NK cells.
  Immunity, 27, 214-227.  
  17164340 J.A.Deane, M.G.Kharas, J.S.Oak, L.N.Stiles, J.Luo, T.I.Moore, H.Ji, C.Rommel, L.C.Cantley, T.E.Lane, and D.A.Fruman (2007).
T-cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling.
  Blood, 109, 2894-2902.  
17483449 J.D.Chang, G.K.Sukhova, P.Libby, E.Schvartz, A.H.Lichtenstein, S.J.Field, C.Kennedy, S.Madhavarapu, J.Luo, D.Wu, and L.C.Cantley (2007).
Deletion of the phosphoinositide 3-kinase p110gamma gene attenuates murine atherosclerosis.
  Proc Natl Acad Sci U S A, 104, 8077-8082.  
17956290 J.S.Oak, M.P.Matheu, I.Parker, M.D.Cahalan, and D.A.Fruman (2007).
Lymphocyte cell motility: the twisting, turning tale of phosphoinositide 3-kinase.
  Biochem Soc Trans, 35, 1109-1113.  
17530707 M.A.Amin, P.J.Mansfield, A.Pakozdi, P.L.Campbell, S.Ahmed, R.J.Martinez, and A.E.Koch (2007).
Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways.
  Arthritis Rheum, 56, 1787-1797.  
17635796 M.Bokarewa, A.Tarkowski, and M.Magnusson (2007).
Pathological survivin expression links viral infections with pathogenesis of erosive rheumatoid arthritis.
  Scand J Immunol, 66, 192-198.  
  17785853 M.Jana, A.Jana, X.Liu, S.Ghosh, and K.Pahan (2007).
Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of I kappa B alpha in anti-inflammatory effect of gemfibrozil in microglia.
  J Immunol, 179, 4142-4152.  
17644738 N.Kim, A.Saudemont, L.Webb, M.Camps, T.Ruckle, E.Hirsch, M.Turner, and F.Colucci (2007).
The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion.
  Blood, 110, 3202-3208.  
17984576 N.Tamura, and K.Haruta (2007).
[Therapeutic potential of phosphoinositide 3-kinase inhibitors in rheumatoid arthritis]
  Nihon Rinsho Meneki Gakkai Kaishi, 30, 369-374.  
17561399 P.K.Vogt, S.Kang, M.A.Elsliger, and M.Gymnopoulos (2007).
Cancer-specific mutations in phosphatidylinositol 3-kinase.
  Trends Biochem Sci, 32, 342-349.  
17916723 P.T.Hawkins, and L.R.Stephens (2007).
PI3Kgamma is a key regulator of inflammatory responses and cardiovascular homeostasis.
  Science, 318, 64-66.  
17804702 Q.W.Fan, C.K.Cheng, T.P.Nicolaides, C.S.Hackett, Z.A.Knight, K.M.Shokat, and W.A.Weiss (2007).
A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma.
  Cancer Res, 67, 7960-7965.  
17968336 S.E.Sweeney, and G.S.Firestein (2007).
Primer: signal transduction in rheumatic disease--a clinician's guide.
  Nat Clin Pract Rheumatol, 3, 651-660.  
17827385 S.Kim, A.Garcia, S.P.Jackson, and S.P.Kunapuli (2007).
Insulin-like growth factor-1 regulates platelet activation through PI3-Kalpha isoform.
  Blood, 110, 4206-4213.  
17963503 S.Shahrara, H.P.Castro-Rueda, G.K.Haines, and A.E.Koch (2007).
Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues.
  Arthritis Res Ther, 9, R112.  
16702948 C.Billottet, V.L.Grandage, R.E.Gale, A.Quattropani, C.Rommel, B.Vanhaesebroeck, and A.Khwaja (2006).
A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16.
  Oncogene, 25, 6648-6659.  
16823479 C.F.Semenkovich (2006).
Insulin resistance and atherosclerosis.
  J Clin Invest, 116, 1813-1822.  
16997136 D.A.Medina-Tato, M.L.Watson, and S.G.Ward (2006).
Leukocyte navigation mechanisms as targets in airway diseases.
  Drug Discov Today, 11, 866-879.  
16680006 D.L.Williams, T.Ozment-Skelton, and C.Li (2006).
Modulation of the phosphoinositide 3-kinase signaling pathway alters host response to sepsis, inflammation, and ischemia/reperfusion injury.
  Shock, 25, 432-439.  
17172449 J.Doukas, W.Wrasidlo, G.Noronha, E.Dneprovskaia, R.Fine, S.Weis, J.Hood, A.Demaria, R.Soll, and D.Cheresh (2006).
Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury.
  Proc Natl Acad Sci U S A, 103, 19866-19871.  
16732722 M.Braddock, and C.Murray (2006).
10th anniversary Inflammation and Immune Diseases Drug Discovery and Development Summit. 20-21 March 2006, New Brunswick, USA.
  Expert Opin Investig Drugs, 15, 721-727.  
16924470 R.Hooft van Huijsduijnen, and C.Rommel (2006).
Decompartmentalizing target validation-thinking outside the pipeline boxes.
  J Mol Med, 84, 802-813.  
16413226 S.G.Ward (2006).
T lymphocytes on the move: chemokines, PI 3-kinase and beyond.
  Trends Immunol, 27, 80-87.  
16310864 T.N.Wells, C.A.Power, J.P.Shaw, and A.E.Proudfoot (2006).
Chemokine blockers--therapeutics in the making?
  Trends Pharmacol Sci, 27, 41-47.  
17080027 T.Rückle, M.K.Schwarz, and C.Rommel (2006).
PI3Kgamma inhibition: towards an 'aspirin of the 21st century'?
  Nat Rev Drug Discov, 5, 903-918.  
16647110 Z.A.Knight, B.Gonzalez, M.E.Feldman, E.R.Zunder, D.D.Goldenberg, O.Williams, R.Loewith, D.Stokoe, A.Balla, B.Toth, T.Balla, W.A.Weiss, R.L.Williams, and K.M.Shokat (2006).
A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.
  Cell, 125, 733-747.
PDB codes: 2chw 2chx 2chz
16127435 D.F.Barber, A.Bartolomé, C.Hernandez, J.M.Flores, C.Redondo, C.Fernandez-Arias, M.Camps, T.Rückle, M.K.Schwarz, S.Rodríguez, C.Martinez-A, D.Balomenos, C.Rommel, and A.C.Carrera (2005).
PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus.
  Nat Med, 11, 933-935.  
16145571 P.S.Ohashi, and J.R.Woodgett (2005).
Modulating autoimmunity: pick your PI3 kinase.
  Nat Med, 11, 924-925.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.