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PDBsum entry 2chw

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Transferase/inhibitor PDB id
2chw
Jmol
Contents
Protein chain
840 a.a. *
Ligands
039
Waters ×8
* Residue conservation analysis
PDB id:
2chw
Name: Transferase/inhibitor
Title: A pharmacological map of the pi3-k family defines a role for p110 alpha in signaling: the structure of complex of phosphoinositide 3-kinase gamma with inhibitor pik-39
Structure: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform. Chain: a. Fragment: human pi-3k gamma catalytic subunit, residues 144-1102. Synonym: phosphoinositide 3-kinase, pi3-kinase p110 subunit gamma, ptdins-3-kinase p110, pi3k, pi3kgamma. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.6Å     R-factor:   0.240     R-free:   0.299
Authors: 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,K.M.Shokat
Key ref:
Z.A.Knight et al. (2006). A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell, 125, 733-747. PubMed id: 16647110 DOI: 10.1016/j.cell.2006.03.035
Date:
16-Mar-06     Release date:   22-May-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

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

 Enzyme reactions 
   Enzyme class 2: E.C.2.7.1.153  - Phosphatidylinositol-4,5-bisphosphate 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
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
ATP
+ 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
= ADP
+ 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
   Enzyme class 3: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ 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  

 

 
    reference    
 
 
DOI no: 10.1016/j.cell.2006.03.035 Cell 125:733-747 (2006)
PubMed id: 16647110  
 
 
A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.
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, K.M.Shokat.
 
  ABSTRACT  
 
Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Structures of Isoform-Selective PI3-K Inhibitors
(A) Crystal structure of ATP in the active site of p110γ, highlighting regions designated as the adenine, affinity, and selectivity pockets. Hydrogen bonds are indicated by arrows.
(B) Alignment of all reported PI3-K inhibitor cocrystal structures. PIK-39 is colored orange and all other inhibitors are colored blue. Met 804 (red) adopts an up conformation in all structures except PIK-39.
(C) Crystal structures and models of isoform-selective PI3-K inhibitors bound to p110γ.
(D) Crystal structures and models of multitargeted PI3-K inhibitors bound to p110γ.
Figure 4.
Figure 4. Biochemical Analysis of the PI3-K Pathway in Fat and Muscle Cells
(A) Western blots of lysates from 3T3-L1 adipocytes or L6 myotubes stimulated with insulin (100 nM) in the presence of PI3-K inhibitors. Phosphorylation sites not specified in the figure: ERK1/2 (p202/204), GSK3α/β (p21/9), rpS6 (p235/236), 4E-BP1 (p37/46).
(B) Inositol lipid levels following insulin stimulation (100 nM) in the presence of PI3-K inhibitors.
(C) Western blots of lysates from L6 myotubes stimulated with LPA (10 μM) in the presence of PI3-K inhibitors.
 
  The above figures are reprinted by permission from Cell Press: Cell (2006, 125, 733-747) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23400000 J.Rodon, R.Dienstmann, V.Serra, and J.Tabernero (2013).
Development of PI3K inhibitors: lessons learned from early clinical trials.
  Nat Rev Clin Oncol, 10, 143-153.  
22358332 B.Vanhaesebroeck, L.Stephens, and P.Hawkins (2012).
PI3K signalling: the path to discovery and understanding.
  Nat Rev Mol Cell Biol, 13, 195-203.  
20626398 A.Eisenreich, and U.Rauch (2011).
PI3K inhibitors in cardiovascular disease.
  Cardiovasc Ther, 29, 29-36.  
20959606 B.J.Lannutti, S.A.Meadows, S.E.Herman, A.Kashishian, B.Steiner, A.J.Johnson, J.C.Byrd, J.W.Tyner, M.M.Loriaux, M.Deininger, B.J.Druker, K.D.Puri, R.G.Ulrich, and N.A.Giese (2011).
CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability.
  Blood, 117, 591-594.  
22037041 D.Benjamin, M.Colombi, C.Moroni, and M.N.Hall (2011).
Rapamycin passes the torch: a new generation of mTOR inhibitors.
  Nat Rev Drug Discov, 10, 868-880.  
21395485 D.W.Bowles, and A.Jimeno (2011).
New phosphatidylinositol 3-kinase inhibitors for cancer.
  Expert Opin Investig Drugs, 20, 507-518.  
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.  
21208444 J.R.Brown, and K.R.Auger (2011).
Phylogenomics of phosphoinositide lipid kinases: perspectives on the evolution of second messenger signaling and drug discovery.
  BMC Evol Biol, 11, 4.  
21048785 J.Werzowa, S.Koehrer, S.Strommer, D.Cejka, T.Fuereder, E.Zebedin, and V.Wacheck (2011).
Vertical inhibition of the mTORC1/mTORC2/PI3K pathway shows synergistic effects against melanoma in vitro and in vivo.
  J Invest Dermatol, 131, 495-503.  
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.  
21035500 M.P.Gratacap, J.Guillermet-Guibert, V.Martin, G.Chicanne, H.Tronchère, F.Gaits-Iacovoni, and B.Payrastre (2011).
Regulation and roles of PI3Kβ, a major actor in platelet signaling and functions.
  Adv Enzyme Regul, 51, 106-116.  
21139583 W.Zhou, S.Guo, and R.R.Gonzalez-Perez (2011).
Leptin pro-angiogenic signature in breast cancer is linked to IL-1 signalling.
  Br J Cancer, 104, 128-137.  
21362552 X.Zhang, O.Vadas, O.Perisic, K.E.Anderson, J.Clark, P.T.Hawkins, L.R.Stephens, and R.L.Williams (2011).
Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism.
  Mol Cell, 41, 567-578.
PDB code: 2y3a
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
20441566 A.Garcia, S.Kim, K.Bhavaraju, S.M.Schoenwaelder, and S.P.Kunapuli (2010).
Role of phosphoinositide 3-kinase beta in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways.
  Biochem J, 429, 369-377.  
  20671809 A.M.Martelli, C.Evangelisti, F.Chiarini, and J.A.McCubrey (2010).
The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients.
  Oncotarget, 1, 89.  
20093402 A.Vaid, R.Ranjan, W.A.Smythe, H.C.Hoppe, and P.Sharma (2010).
PfPI3K, a phosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin trafficking.
  Blood, 115, 2500-2507.  
20379207 B.Vanhaesebroeck, J.Guillermet-Guibert, M.Graupera, and B.Bilanges (2010).
The emerging mechanisms of isoform-specific PI3K signalling.
  Nat Rev Mol Cell Biol, 11, 329-341.  
20148286 C.Y.Liew, X.H.Ma, and C.W.Yap (2010).
Consensus model for identification of novel PI3K inhibitors in large chemical library.
  J Comput Aided Mol Des, 24, 131-141.  
20081091 D.R.Soond, E.Bjørgo, K.Moltu, V.Q.Dale, D.T.Patton, K.M.Torgersen, F.Galleway, B.Twomey, J.Clark, J.S.Gaston, K.Taskén, P.Bunyard, and K.Okkenhaug (2010).
PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans.
  Blood, 115, 2203-2213.  
20729870 D.X.Kong, and T.Yamori (2010).
ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system.
  Acta Pharmacol Sin, 31, 1189-1197.  
20176501 F.Hollande, J.Pannequin, and D.Joubert (2010).
The long road to colorectal cancer therapy: searching for the right signals.
  Drug Resist Updat, 13, 44-56.  
  20581473 H.Carter, J.Samayoa, R.H.Hruban, and R.Karchin (2010).
Prioritization of driver mutations in pancreatic cancer using cancer-specific high-throughput annotation of somatic mutations (CHASM).
  Cancer Biol Ther, 10, 582-587.  
19864464 I.C.Fields, S.M.King, E.Shteyn, R.S.Kang, and H.Fölsch (2010).
Phosphatidylinositol 3,4,5-trisphosphate localization in recycling endosomes is necessary for AP-1B-dependent sorting in polarized epithelial cells.
  Mol Biol Cell, 21, 95.  
19996317 J.Roux, M.Carles, H.Koh, A.Goolaerts, M.T.Ganter, B.B.Chesebro, M.Howard, B.T.Houseman, W.Finkbeiner, K.M.Shokat, A.C.Paquet, M.A.Matthay, and J.F.Pittet (2010).
Transforming growth factor beta1 inhibits cystic fibrosis transmembrane conductance regulator-dependent cAMP-stimulated alveolar epithelial fluid transport via a phosphatidylinositol 3-kinase-dependent mechanism.
  J Biol Chem, 285, 4278-4290.  
20463662 J.Sasaki, S.Kofuji, R.Itoh, T.Momiyama, K.Takayama, H.Murakami, S.Chida, Y.Tsuya, S.Takasuga, S.Eguchi, K.Asanuma, Y.Horie, K.Miura, E.M.Davies, C.Mitchell, M.Yamazaki, H.Hirai, T.Takenawa, A.Suzuki, and T.Sasaki (2010).
The PtdIns(3,4)P(2) phosphatase INPP4A is a suppressor of excitotoxic neuronal death.
  Nature, 465, 497-501.  
21075311 J.Tan, P.L.Lee, Z.Li, X.Jiang, Y.C.Lim, S.C.Hooi, and Q.Yu (2010).
B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer.
  Cancer Cell, 18, 459-471.  
20854263 K.Aoyagi, M.Ohara-Imaizumi, C.Nishiwaki, Y.Nakamichi, and S.Nagamatsu (2010).
Insulin/phosphoinositide 3-kinase pathway accelerates the glucose-induced first-phase insulin secretion through TrpV2 recruitment in pancreatic β-cells.
  Biochem J, 432, 375-386.  
20085938 K.D.Courtney, R.B.Corcoran, and J.A.Engelman (2010).
The PI3K pathway as drug target in human cancer.
  J Clin Oncol, 28, 1075-1083.  
21079586 M.Bucci, C.Goodman, and T.L.Sheppard (2010).
A decade of chemical biology.
  Nat Chem Biol, 6, 847-854.  
20194733 M.Dail, Q.Li, A.McDaniel, J.Wong, K.Akagi, B.Huang, H.C.Kang, S.C.Kogan, K.Shokat, L.Wolff, B.S.Braun, and K.Shannon (2010).
Mutant Ikzf1, KrasG12D, and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents.
  Proc Natl Acad Sci U S A, 107, 5106-5111.  
  20657741 M.R.Janes, and D.A.Fruman (2010).
Targeting TOR dependence in cancer.
  Oncotarget, 1, 69-76.  
20713702 M.Sun, P.Hillmann, B.T.Hofmann, J.R.Hart, and P.K.Vogt (2010).
Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.
  Proc Natl Acad Sci U S A, 107, 15547-15552.  
20144757 N.Mizushima, T.Yoshimori, and B.Levine (2010).
Methods in mammalian autophagy research.
  Cell, 140, 313-326.  
20176047 N.T.Ihle, and G.Powis (2010).
Inhibitors of phosphatidylinositol-3-kinase in cancer therapy.
  Mol Aspects Med, 31, 135-144.  
20510927 N.Y.Hsu, O.Ilnytska, G.Belov, M.Santiana, Y.H.Chen, P.M.Takvorian, C.Pau, H.van der Schaar, N.Kaushik-Basu, T.Balla, C.E.Cameron, E.Ehrenfeld, F.J.van Kuppeveld, and N.Altan-Bonnet (2010).
Viral reorganization of the secretory pathway generates distinct organelles for RNA replication.
  Cell, 141, 799-811.  
  21179398 O.Schmidt-Kittler, J.Zhu, J.Yang, G.Liu, W.Hendricks, C.Lengauer, S.B.Gabelli, K.W.Kinzler, B.Vogelstein, D.L.Huso, and S.Zhou (2010).
PI3Kα Inhibitors That Inhibit Metastasis.
  Oncotarget, 1, 339-348.  
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.  
20189098 P.E.Thompson, I.G.Jennings, and J.A.Pinson (2010).
Inflammatory twins from PI3K gang brought to justice?
  Chem Biol, 17, 101-102.  
20484502 P.Spuul, G.Balistreri, L.Kääriäinen, and T.Ahola (2010).
Phosphatidylinositol 3-kinase-, actin-, and microtubule-dependent transport of Semliki Forest Virus replication complexes from the plasma membrane to modified lysosomes.
  J Virol, 84, 7543-7557.  
20609406 P.Workman, and I.Collins (2010).
Probing the probes: fitness factors for small molecule tools.
  Chem Biol, 17, 561-577.  
20081818 P.Workman, and R.L.van Montfort (2010).
PI(3) kinases: revealing the delta lady.
  Nat Chem Biol, 6, 82-83.  
21062993 Q.W.Fan, C.Cheng, C.Hackett, M.Feldman, B.T.Houseman, T.Nicolaides, D.Haas-Kogan, C.D.James, S.A.Oakes, J.Debnath, K.M.Shokat, and W.A.Weiss (2010).
Akt and autophagy cooperate to promote survival of drug-resistant glioma.
  Sci Signal, 3, ra81.  
  20535652 Q.W.Fan, and W.A.Weiss (2010).
Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance.
  Curr Top Microbiol Immunol, 347, 279-296.  
19919182 R.Batra-Safferling, J.Granzin, S.Mödder, S.Hoffmann, and D.Willbold (2010).
Structural studies of the phosphatidylinositol 3-kinase (PI3K) SH3 domain in complex with a peptide ligand: role of the anchor residue in ligand binding.
  Biol Chem, 391, 33-42.
PDB codes: 3i5r 3i5s
19638643 R.V.Rajala (2010).
Phosphoinositide 3-kinase signaling in the vertebrate retina.
  J Lipid Res, 51, 4.  
19834495 R.W.Matheny, and M.L.Adamo (2010).
PI3K p110 alpha and p110 beta have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts.
  Cell Death Differ, 17, 677-688.  
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.  
20799872 S.Carvalho, and F.Schmitt (2010).
Potential role of PI3K inhibitors in the treatment of breast cancer.
  Future Oncol, 6, 1251-1263.  
20534477 S.H.Lee, G.Poulogiannis, S.Pyne, S.Jia, L.Zou, S.Signoretti, M.Loda, L.C.Cantley, and T.M.Roberts (2010).
A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice.
  Proc Natl Acad Sci U S A, 107, 11002-11007.  
20499346 S.K.Martin, S.Fitter, L.F.Bong, J.J.Drew, S.Gronthos, P.R.Shepherd, and A.C.Zannettino (2010).
NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells.
  J Bone Miner Res, 25, 2126-2137.  
  20953381 S.M.Ivison, M.A.Khan, N.R.Graham, L.A.Shobab, Y.Yao, A.Kifayet, L.M.Sly, and T.S.Steiner (2010).
The p110α and p110β isoforms of class I phosphatidylinositol 3-kinase are involved in toll-like receptor 5 signaling in epithelial cells.
  Mediators Inflamm, 2010, 0.  
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.  
  19951971 S.Park, N.Chapuis, J.Tamburini, V.Bardet, P.Cornillet-Lefebvre, L.Willems, A.Green, P.Mayeux, C.Lacombe, and D.Bouscary (2010).
Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia.
  Haematologica, 95, 819-828.  
20169382 Y.Li, Y.Wang, and F.Zhang (2010).
Pharmacophore modeling and 3D-QSAR analysis of phosphoinositide 3-kinase p110alpha inhibitors.
  J Mol Model, 16, 1449-1460.  
19897488 Y.Ng, G.Ramm, J.G.Burchfield, A.C.Coster, J.Stöckli, and D.E.James (2010).
Cluster analysis of insulin action in adipocytes reveals a key role for Akt at the plasma membrane.
  J Biol Chem, 285, 2245-2257.  
20620998 Y.Xu, J.W.Hill, M.Fukuda, L.Gautron, J.W.Sohn, K.W.Kim, C.E.Lee, M.J.Choi, D.A.Lauzon, H.Dhillon, B.B.Lowell, J.M.Zigman, J.J.Zhao, and J.K.Elmquist (2010).
PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis.
  Cell Metab, 12, 88-95.  
20361045 Z.Ding, J.Liang, J.Li, Y.Lu, V.Ariyaratna, Z.Lu, M.A.Davies, J.K.Westwick, and G.B.Mills (2010).
Physical association of PDK1 with AKT1 is sufficient for pathway activation independent of membrane localization and phosphatidylinositol 3 kinase.
  PLoS One, 5, e9910.  
20689039 Z.Sun, Z.Li, and Y.Zhang (2010).
Adult testicular dysgenesis of Inhba conditional knockout mice may also be caused by disruption of cross-talk between Leydig cells and germ cells.
  Proc Natl Acad Sci U S A, 107, E135; author reply E136.  
19143676 A.Rohrbach, I.Rubio, M.Bulgay-Moerschel, C.Koenig, T.G.Poehlmann, U.R.Markert, and M.Gruen (2009).
Selective downregulation of phosphoinositide 3-kinase alpha in leukocytes during pregnancy.
  Am J Reprod Immunol, 61, 130-135.  
19186178 A.Ruhland, and P.E.Kima (2009).
Activation of PI3K/Akt signaling has a dominant negative effect on IL-12 production by macrophages infected with Leishmania amazonensis promastigotes.
  Exp Parasitol, 122, 28-36.  
19509266 A.Smith, J.Blois, H.Yuan, E.Aikawa, C.Ellson, J.L.Figueiredo, R.Weissleder, R.Kohler, M.B.Yaffe, L.C.Cantley, and L.Josephson (2009).
The antiproliferative cytostatic effects of a self-activating viridin prodrug.
  Mol Cancer Ther, 8, 1666-1675.  
20011115 B.Sahay, R.L.Patsey, C.H.Eggers, J.C.Salazar, J.D.Radolf, and T.J.Sellati (2009).
CD14 signaling restrains chronic inflammation through induction of p38-MAPK/SOCS-dependent tolerance.
  PLoS Pathog, 5, e1000687.  
19150980 C.C.Thoreen, S.A.Kang, J.W.Chang, Q.Liu, J.Zhang, Y.Gao, L.J.Reichling, T.Sim, D.M.Sabatini, and N.S.Gray (2009).
An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1.
  J Biol Chem, 284, 8023-8032.  
19225459 C.C.Wang, M.Cirit, and J.M.Haugh (2009).
PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk.
  Mol Syst Biol, 5, 246.  
  18523868 C.García-Echeverría (2009).
Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways.
  Purinergic Signal, 5, 117-125.  
19076776 C.K.Cheng, Q.W.Fan, and W.A.Weiss (2009).
PI3K signaling in glioma--animal models and therapeutic challenges.
  Brain Pathol, 19, 112-120.  
19603422 C.Schild, M.Wirth, M.Reichert, R.M.Schmid, D.Saur, and G.Schneider (2009).
PI3K signaling maintains c-myc expression to regulate transcription of E2F1 in pancreatic cancer cells.
  Mol Carcinog, 48, 1149-1158.  
19290933 D.A.Fruman, and G.Bismuth (2009).
Fine tuning the immune response with PI3K.
  Immunol Rev, 228, 253-272.  
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.  
19509054 E.Kingham, and M.Welham (2009).
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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.
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Targeting mammalian target of rapamycin (mTOR) for health and diseases.
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Potential therapeutic applications of autophagy.
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17711503 D.Kong, and T.Yamori (2007).
ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms.
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Use of pharmacokinetic/pharmacodynamic biomarkers to support rational cancer drug development.
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17581634 E.A.Papakonstanti, A.J.Ridley, and B.Vanhaesebroeck (2007).
The p110delta isoform of PI 3-kinase negatively controls RhoA and PTEN.
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17905659 G.G.Chiang, and R.T.Abraham (2007).
Targeting the mTOR signaling network in cancer.
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17456549 H.K.Bone, and M.J.Welham (2007).
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17541179 H.Nakamura, S.Dan, T.Akashi, M.Unno, and T.Yamori (2007).
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17379147 H.Yuan, K.R.Barnes, R.Weissleder, L.Cantley, and L.Josephson (2007).
Covalent reactions of wortmannin under physiological conditions.
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17827393 I.Hers (2007).
Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kalpha pathway.
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T-cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling.
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17486056 J.Lackey, J.Barnett, L.Davidson, I.H.Batty, N.R.Leslie, and C.P.Downes (2007).
Loss of PTEN selectively desensitizes upstream IGF1 and insulin signaling.
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17462572 J.Yang, A.Shamji, S.Matchacheep, and S.L.Schreiber (2007).
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17581609 K.T.Doepfner, O.Spertini, and A.Arcaro (2007).
Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway.
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17562705 L.M.Ballou, E.S.Selinger, J.Y.Choi, D.G.Drueckhammer, and R.Z.Lin (2007).
Inhibition of mammalian target of rapamycin signaling by 2-(morpholin-1-yl)pyrimido[2,1-alpha]isoquinolin-4-one.
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17568801 M.Kawasumi, and P.Nghiem (2007).
Chemical genetics: elucidating biological systems with small-molecule compounds.
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17204467 M.P.Storm, H.K.Bone, C.G.Beck, P.Y.Bourillot, V.Schreiber, T.Damiano, A.Nelson, P.Savatier, and M.J.Welham (2007).
Regulation of Nanog expression by phosphoinositide 3-kinase-dependent signaling in murine embryonic stem cells.
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17996064 M.Torvinen, H.Campwala, and I.Kilty (2007).
The role of IFN-gamma in regulation of IFN-gamma-inducible protein 10 (IP-10) expression in lung epithelial cell and peripheral blood mononuclear cell co-cultures.
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17240336 N.R.Leslie, X.Yang, C.P.Downes, and C.J.Weijer (2007).
PtdIns(3,4,5)P(3)-dependent and -independent roles for PTEN in the control of cell migration.
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17561399 P.K.Vogt, S.Kang, M.A.Elsliger, and M.Gymnopoulos (2007).
Cancer-specific mutations in phosphatidylinositol 3-kinase.
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17473931 P.Várnai, and T.Balla (2007).
Visualization and manipulation of phosphoinositide dynamics in live cells using engineered protein domains.
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A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma.
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17301796 R.N.Hannoush (2007).
Probing cellular systems with chemistry.
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17452018 S.G.Dann, A.Selvaraj, and G.Thomas (2007).
mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer.
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Insulin-like growth factor-1 regulates platelet activation through PI3-Kalpha isoform.
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Application of meso scale technology for the measurement of phosphoproteins in human tumor xenografts.
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17673465 S.M.Schoenwaelder, A.Ono, S.Sturgeon, S.M.Chan, P.Mangin, M.J.Maxwell, S.Turnbull, M.Mulchandani, K.Anderson, G.Kauffenstein, G.W.Rewcastle, J.Kendall, C.Gachet, H.H.Salem, and S.P.Jackson (2007).
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The PI3K inhibitor arsenal: choose your weapon!
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Structural insights into activation of phosphatidylinositol 4-kinase (Pik1) by yeast frequenin (Frq1).
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PDB code: 2ju0
17442716 T.Utermark, B.S.Schaffhausen, T.M.Roberts, and J.J.Zhao (2007).
The p110alpha isoform of phosphatidylinositol 3-kinase is essential for polyomavirus middle T antigen-mediated transformation.
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17402792 V.P.Krymskaya (2007).
Targeting the phosphatidylinositol 3-kinase pathway in airway smooth muscle: rationale and promise.
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Recognizing and exploiting differences between RNAi and small-molecule inhibitors.
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Chemical genetics: where genetics and pharmacology meet.
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17947987 Z.A.Knight, M.E.Feldman, A.Balla, T.Balla, and K.M.Shokat (2007).
A membrane capture assay for lipid kinase activity.
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16864657 A.Van Keymeulen, K.Wong, Z.A.Knight, C.Govaerts, K.M.Hahn, K.M.Shokat, and H.R.Bourne (2006).
To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front.
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Phosphatidylinositol 4-kinase IIIbeta regulates the transport of ceramide between the endoplasmic reticulum and Golgi.
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PtdIns3P binding to the PX domain of p40phox is a physiological signal in NADPH oxidase activation.
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16915295 D.M.Sabatini (2006).
mTOR and cancer: insights into a complex relationship.
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16847462 J.A.Engelman, J.Luo, and L.C.Cantley (2006).
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.
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17060635 J.J.Zhao, H.Cheng, S.Jia, L.Wang, O.V.Gjoerup, A.Mikami, and T.M.Roberts (2006).
The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation.
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17057752 K.A.Janes, and M.B.Yaffe (2006).
Data-driven modelling of signal-transduction networks.
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16929325 K.Imai, and A.Takaoka (2006).
Comparing antibody and small-molecule therapies for cancer.
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17167487 M.Hafner, A.Schmitz, I.Grüne, S.G.Srivatsan, B.Paul, W.Kolanus, T.Quast, E.Kremmer, I.Bauer, and M.Famulok (2006).
Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance.
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17099362 M.R.Grimmer, and W.A.Weiss (2006).
Childhood tumors of the nervous system as disorders of normal development.
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17080027 T.Rückle, M.K.Schwarz, and C.Rommel (2006).
PI3Kgamma inhibition: towards an 'aspirin of the 21st century'?
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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 code is shown on the right.