PI3K signalling: The path to discovery and understanding

Nature Reviews Molecular Cell Biology

Volumn 13, Issue 3, 2012, Pages 195-203

  Vanhaesebroeck, Bart ^a   Stephens, Len ^b   Hawkins, Phillip ^b  

^a QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^b BABRAHAM INSTITUTE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

PHOSPHATIDYLINOSITOL 3 KINASE;

ENZYME ACTIVITY; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; ENZYME INHIBITORS; HUMANS; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PHOSPHORYLATION; PROTEIN STRUCTURE, TERTIARY; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION;

EID: 84857406235     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm3290     Document Type: Review

References (174)

1. Sugimoto, Y., Whitman, M., Cantley, L. C. & Erikson, R. L. Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc. Natl Acad. Sci. USA 81, 2117-2121 (1984). (Pubitemid 14146614)
2. Macara, I. G., Marinetti, G. V. & Balduzzi, P. C. Transforming protein of avian sarcoma virus UR2 is associated with phosphatidylinositol kinase activity: possible role in tumorigenesis. Proc. Natl Acad. Sci. USA 81, 2728-2732 (1984). (Pubitemid 14109332)
3. Whitman, M., Kaplan, D. R., Schaffhausen, B., Cantley, L. & Roberts, T. M. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315, 239-242 (1985). (Pubitemid 15064453)
4. Kaplan, D. R. et al. Phosphatidylinositol metabolism and polyoma-mediated transformation. Proc. Natl Acad. Sci. USA 83, 3624-3628 (1986). (Pubitemid 16062337)
5. Kaplan, D. R. et al. Common elements in growth factor stimulation and oncogenic transformation: 85 KD phosphoprotein and phosphatidylinositol kinase activity. Cell 50, 1021-1029 (1987).
6. Whitman, M., Downes, C. P., Keeler, M., Keller, T. & Cantley, L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 332, 644-646 (1988).
7. Traynor-Kaplan, A. E., Harris, A. L., Thompson, B. L., Taylor, P. & Sklar, L. A. An inositol tetrakisphosphate-containing phospholipid in activated neutrophils. Nature 334, 353-356 (1988).
8. Auger, K. R., Serunian, L. A., Soltoff, S. P., Libby, P. & Cantley, L. C. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57, 167-175 (1989). (Pubitemid 19098878)
9. Traynor-Kaplan, A. E. et al. Transient increase in phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol trisphosphate during activation of human neutrophils. J. Biol. Chem. 264, 15668-15673 (1989). (Pubitemid 19242949)
10. Stephens, L., Hawkins, P. T. & Downes, C. P. Metabolic and structural evidence for the existence of a third species of polyphosphoinositide in cells: d-phosphatidyl-myo-inositol 3-phosphate. Biochem. J. 259, 267-276 (1989). (Pubitemid 19100524)
11. Ruderman, N. B., Kapeller, R., White, M. F. & Cantley, L. C. Activation of phosphatidylinositol 3-kinase by insulin. Proc. Natl Acad. Sci. USA 87, 1411-1415 (1990).
12. Stephens, L. R., Hughes, K. T. & Irvine, R. F. Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils. Nature 351, 33-39 (1991). (Pubitemid 21896524)
13. Hawkins, P. T., Jackson, T. R. & Stephens, L. R. Platelet-derived growth factor stimulates synthesis of PtdIns(3,4,5)P3 by activating a PtdIns(4,5)P2 3-OH kinase. Nature 358, 157-159 (1992).
14. Divecha, N. & Irvine, R. F. Phospholipid signaling. Cell 80, 269-278 (1995).
15. Carpenter, C. L. et al. Purification and characterization of phosphoinositide 3-kinase from rat liver. J. Biol. Chem. 265, 19704-19711 (1990). (Pubitemid 120013919)
16. Morgan, S. J., Smith, A. D. & Parker, P. J. Purification and characterization of bovine brain type I phosphatidylinositol kinase. Eur. J. Biochem. 191, 761-767 (1990). (Pubitemid 20265787)
17. Shibasaki, F., Homma, Y. & Takenawa, T. Two types of phosphatidylinositol 3-kinase from bovine thymus. Monomer and heterodimer form. J. Biol. Chem. 266, 8108-8114 (1991). (Pubitemid 21906483)
18. Fry, M. J. et al. Purification and characterization of a phosphatidylinositol 3-kinase complex from bovine brain by using phosphopeptide affinity columns. Biochem. J. 288, 383-393 (1992).
19. Courtneidge, S. A. & Heber, A. An 81 kd protein complexed with middle T antigen and pp60c-src: a possible phosphatidylinositol kinase. Cell 50, 1031-1037 (1987).
20. Otsu, M. et al. Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase. Cell 65, 91-104 (1991). (Pubitemid 121001217)
21. Escobedo, J. A. et al. cDNA cloning of a novel 85 kd protein that has SH2 domains and regulates binding of PI3-kinase to the PDGF β-receptor. Cell 65, 75-82 (1991). (Pubitemid 121001215)
22. Skolnik, E. Y. et al. Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 65, 83-90 (1991). (Pubitemid 121001216)
23. Hiles, I. D. et al. Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell 70, 419-429 (1992).
24. Backer, J. M. et al. Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 11, 3469-3479 (1992).
25. Herman, P. K. & Emr, S. D. Characterization of Vps34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Mol. Cell. Biol. 10, 6742-6754 (1990). (Pubitemid 120004619)
26. Schu, P. V. et al. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260, 88-91 (1993). (Pubitemid 23122750)
27. Stephens, L. et al. Characterization of a phosphatidylinositol-specific phosphoinositide 3-kinase from mammalian cells. Curr. Biol. 4, 203-214 (1994).
28. Morris, J. Z., Tissenbaum, H. A. & Ruvkun, G. A phosphatidylinositol- 3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382, 536-539 (1996). (Pubitemid 26260694)
29. MacDougall, L. K., Domin, J. & Waterfield, M. D. A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction. Curr. Biol. 5, 1404-1415 (1995). (Pubitemid 3008923)
30. Zhou, K., Takegawa, K., Emr, S. D. & Firtel, R. A. A phosphatidylinositol (PI) kinase gene family in Dictyostelium discoideum: biological roles of putative mammalian p110 and yeast Vps34p PI 3-kinase homologs during growth and development. Mol. Cell. Biol. 15, 5645-5656 (1995).
31. Stoyanov, B. et al. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science 269, 690-693 (1995).
32. 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). (Pubitemid 24184690)
33. Stephens, L. R. et al. The Gβγ sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89, 105-114 (1997). (Pubitemid 27180590)
34. Stack, J. H., Herman, P. K., Schu, P. V. & Emr, S. D. A membrane-associated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J. 12, 2195-2204 (1993). (Pubitemid 23157734)
35. Virbasius, J. V., Guilherme, A. & Czech, M. P. Mouse p170 is a novel phosphatidylinositol 3-kinase containing a C2 domain. J. Biol. Chem. 271, 13304-13307 (1996).
36. Domin, J. et al. Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin. Biochem. J. 326, 139-147 (1997). (Pubitemid 27386928)
37. Arcaro, A. et al. Human phosphoinositide 3-kinase C2β, the role of calcium and the C2 domain in enzyme activity. J. Biol. Chem. 273, 33082-33090 (1998). (Pubitemid 28557705)
38. Ono, F. et al. A novel class II phosphoinositide 3-kinase predominantly expressed in the liver and its enhanced expression during liver regeneration. J. Biol. Chem. 273, 7731-7736 (1998). (Pubitemid 28152804)
39. Misawa, H. et al. Cloning and characterization of a novel class II phosphoinositide 3-kinase containing C2 domain. Biochem. Biophys. Res. Commun. 244, 531-539 (1998). (Pubitemid 28414116)
40. Maffucci, T., Brancaccio, A., Piccolo, E., Stein, R. C. & Falasca, M. Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation. EMBO J. 22, 4178-4189 (2003). (Pubitemid 37021746)
41. Zvelebil, M. J. et al. Structural and functional diversity of phosphoinositide 3-kinases. Philos. Trans. R. Soc. Lond. B 351, 217-223 (1996). (Pubitemid 126745332)
42. Vanhaesebroeck, B., Leevers, S. J., Panayotou, G. & Waterfield, M. D. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem. Sci. 22, 267-272 (1997). (Pubitemid 27310948)
43. Sjolander, A., Yamamoto, K., Huber, B. E. & Lapetina, E. G. Association of p21ras with phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA 88, 7908-7912 (1991).
44. Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527-532 (1994). (Pubitemid 24264918)
45. Kodaki, T. et al. The activation of phosphatidylinositol 3-kinase by Ras. Curr. Biol. 4, 798-806 (1994).
46. Wiesinger, D., Gubler, H. U., Haefliger, W. & Hauser, D. Antiinflammatory activity of the new mould metabolite 11-desacetoxy-wortmannin and of some of its derivatives. Experientia 30, 135-136 (1974).
47. Arcaro, A. & Wymann, M. P. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem. J. 296, 297-301 (1993). (Pubitemid 23350826)
48. 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). (Pubitemid 23358203)
49. Okada, T., Sakuma, L., Fukui, Y., Hazeki, O. & Ui, M. Blockage of chemotactic peptide-induced stimulation of neutrophils by wortmannin as a result of selective inhibition of phosphatidylinositol 3-kinase. J. Biol. Chem. 269, 3563-3567 (1994).
50. Powis, G. et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res. 54, 2419-2423 (1994).
51. Thelen, M., Wymann, M. P. & Langen, H. Wortmannin binds specifically to 1-phosphatidylinositol 3-kinase while inhibiting guanine nucleotide-binding protein-coupled receptor signaling in neutrophil leukocytes. Proc. Natl Acad. Sci. USA 91, 4960-4964 (1994). (Pubitemid 24177770)
52. Vlahos, C. J., Matter, W. F., Hui, K. Y. & Brown, R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1- benzopyran-4-one (LY294002). J. Biol. Chem. 269, 5241-5248 (1994).
53. Kotani, K. et al. Involvement of phosphoinositide 3-kinase in insulin-or IGF-1-induced membrane ruffling. EMBO J. 13, 2313-2321 (1994). (Pubitemid 24157606)
54. Roche, S., Koegl, M. & Courtneidge, S. A. The phosphatidylinositol 3-kinase α is required for DNA synthesis induced by some, but not all, growth factors. Proc. Natl Acad. Sci. USA 91, 9185-9189 (1994).
55. Kazlauskas, A. & Cooper, J. A. Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins. Cell 58, 1121-1133 (1989). (Pubitemid 19238189)
56. Fantl, W. J. et al. Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways. Cell 69, 413-423 (1992).
57. Coughlin, S. R., Escobedo, J. A. & Williams, L. T. Role of phosphatidylinositol kinase in PDGF receptor signal transduction. Science 243, 1191-1194 (1989). (Pubitemid 19081146)
58. Hara, K. et al. 1-Phosphatidylinositol 3-kinase activity is required for insulin-stimulated glucose transport but not for RAS activation in CHO cells. Proc. Natl Acad. Sci. USA 91, 7415-7419 (1994).
59. Okada, T., Kawano, Y., Sakakibara, T., Hazeki, O. & Ui, M. Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J. Biol. Chem. 269, 3568-3573 (1994).
60. Wennstrom, S. et al. Activation of phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling. Curr. Biol. 4, 385-393 (1994).
61. Wennstrom, S. et al. Membrane ruffling and chemotaxis transduced by the PDGF β-receptor require the binding site for phosphatidylinositol 3′ kinase. Oncogene 9, 651-660 (1994). (Pubitemid 24041546)
62. Wymann, M. & Arcaro, A. Platelet-derived growth factor-induced phosphatidylinositol 3-kinase activation mediates actin rearrangements in fibroblasts. Biochem. J. 298, 517-520 (1994). (Pubitemid 24085171)
63. Haslam, R. J., Koide, H. B. & Hemmings, B. A. Pleckstrin domain homology. Nature 363, 309-310 (1993).
64. Mayer, B. J., Ren, R., Clark, K. L. & Baltimore, D. A putative modular domain present in diverse signaling proteins. Cell 73, 629-630 (1993). (Pubitemid 23159003)
65. Harlan, J. E., Hajduk, P. J., Yoon, H. S. & Fesik, S. W. Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate. Nature 371, 168-170 (1994). (Pubitemid 24284017)
66. Burgering, B. M. & Coffer, P. J. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376, 599-602 (1995).
67. Franke, T. F. et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81, 727-736 (1995).
68. Alessi, D. R. et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr. Biol. 7, 776-789 (1997). (Pubitemid 27441832)
69. Stephens, L. et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279, 710-714 (1998). (Pubitemid 28144551)
70. Alessi, D. R. et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr. Biol. 7, 261-269 (1997). (Pubitemid 27176852)
71. Stokoe, D. et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 277, 567-570 (1997). (Pubitemid 27369005)
72. Alessi, D. R. et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15, 6541-6551 (1996). (Pubitemid 26413787)
73. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098-1101 (2005). (Pubitemid 40262113)
74. Alessi, D. R., Caudwell, F. B., Andjelkovic, M., Hemmings, B. A. & Cohen, P. Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 399, 333-338 (1996). (Pubitemid 26426877)
75. Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. & Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785-789 (1995). (Pubitemid 26004411)
76. Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231-241 (1997). (Pubitemid 27456390)
77. del Peso, L., Gonzalez-Garcia, M., Page, C., Herrera, R. & Nunez, G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278, 687-689 (1997). (Pubitemid 27464966)
78. Zhou, B. P. et al. Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nature Cell Biol. 3, 245-52 (2001). (Pubitemid 32201319)
79. Viglietto, G. et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nature Med. 8, 1136-1144 (2002). (Pubitemid 35175969)
80. Shin, I. et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization. Nature Med. 8, 1145-1152 (2002). (Pubitemid 35175970)
81. Liang, J. et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nature Med. 8, 1153-1160 (2002). (Pubitemid 35175971)
82. Kane, S. et al. A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J. Biol. Chem. 277, 22115-22118 (2002). (Pubitemid 34967174)
83. Bruss, M. D., Arias, E. B., Lienhard, G. E. & Cartee, G. D. Increased phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity. Diabetes 54, 41-50 (2005). (Pubitemid 40105093)
84. Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994-999 (1997). (Pubitemid 27485694)
85. Paradis, S. & Ruvkun, G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev. 12, 2488-2498 (1998). (Pubitemid 28406952)
86. Kops, G. J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398, 630-634 (1999). (Pubitemid 29183692)
87. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868 (1999). (Pubitemid 29165088)
88. Biggs, W. H. 3rd, Meisenhelder, J., Hunter, T., Cavenee, W. K. & Arden, K. C. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc. Natl Acad. Sci. USA 96, 7421-7426 (1999). (Pubitemid 29299677)
89. Guo, S. et al. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J. Biol. Chem. 274, 17184-17192 (1999). (Pubitemid 129519053)
90. Rena, G., Guo, S., Cichy, S. C., Unterman, T. G. & Cohen, P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J. Biol. Chem. 274, 17179-17183 (1999).
91. Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol. 4, 648-657 (2002). (Pubitemid 34993700)
92. Potter, C. J., Pedraza, L. G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol. 4, 658-665 (2002). (Pubitemid 34993701)
93. Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151-162 (2002). (Pubitemid 34876569)
94. Hawkins, P. T. et al. PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase. Curr. Biol. 5, 393-403 (1995).
95. Cheatham, B. et al. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol. Cell. Biol. 14, 4902-4911 (1994). (Pubitemid 24196839)
96. Chung, J., Grammer, T. C., Lemon, K. P., Kazlauskas, A. & Blenis, J. PDGF-and insulin-dependent pp70S6k activation mediated by phosphatidylinositol- 3-OH kinase. Nature 370, 71-75 (1994).
97. Welsh, G. I., Foulstone, E. J., Young, S. W., Tavare, J. M. & Proud, C. G. Wortmannin inhibits the effects of insulin and serum on the activities of glycogen synthase kinase-3 and mitogen-activated protein kinase. Biochem. J. 303, 15-20 (1994). (Pubitemid 24302892)
98. Andjelkovic, M. et al. Role of translocation in the activation and function of protein kinase B. J. Biol. Chem. 272, 31515-31524 (1997). (Pubitemid 28013293)
99. Venkateswarlu, K., Oatey, P. B., Tavare, J. M. & Cullen, P. J. Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes requires phosphatidylinositol 3-kinase. Curr. Biol. 8, 463-466 (1998). (Pubitemid 28181124)
100. Li, Z. et al. Phosphatidylinositol 3-kinaseγ activates Bruton's tyrosine kinase in concert with Src family kinases. Proc. Natl Acad. Sci. USA 94, 13820-13825 (1997). (Pubitemid 28009668)
101. Isakoff, S. J. et al. Identification and analysis of PH domain-containing targets of phosphatidylinositol 3-kinase using a novel in vivo assay in yeast. EMBO J. 17, 5374-5387 (1998). (Pubitemid 28427051)
102. Dowler, S. et al. Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. Biochem. J. 351, 19-31 (2000).
103. Klarlund, J. K. et al. Signaling by phosphoinositide-3,4,5-trisphosphate through proteins containing pleckstrin and Sec7 homology domains. Science 275, 1927-1930 (1997). (Pubitemid 27148813)
104. Welch, H. C. et al. P-Rex1, a PtdIns(3,4,5)P3-and Gβγ- regulated guanine-nucleotide exchange factor for Rac. Cell 108, 809-821 (2002). (Pubitemid 34327532)
105. Krugmann, S. et al. Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices. Mol. Cell 9, 95-108 (2002). (Pubitemid 34127774)
106. Salim, K. et al. Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton's tyrosine kinase. EMBO J. 15, 6241-6250 (1996). (Pubitemid 26397897)
107. Varnai, P. & Balla, T. Visualization of phosphoinositides that bind pleckstrin homology domains: calcium-and agonist-induced dynamic changes and relationship to myo-[3H]inositol-labeled phosphoinositide pools. J. Cell. Biol. 143, 501-510 (1998). (Pubitemid 28487866)
108. Servant, G. et al. Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287, 1037-1040 (2000). (Pubitemid 30094359)
109. Meili, R. et al. Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium. EMBO J. 18, 2092-2105 (1999). (Pubitemid 29179167)
110. Stenmark, H., Aasland, R., Toh, B. H. & D'Arrigo, A. Endosomal localization of the autoantigen EEA1 is mediated by a zinc-binding FYVE finger. J. Biol. Chem. 271, 24048-24054 (1996).
111. Simonsen, A. et al. EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature 394, 494-498 (1998). (Pubitemid 28373962)
112. Gaullier, J. M. et al. FYVE fingers bind PtdIns(3)P. Nature 394, 432-433 (1998).
113. Patki, V., Lawe, D. C., Corvera, S., Virbasius, J. V. & Chawla, A. A functional PtdIns(3)P-binding motif. Nature 394, 433-434 (1998).
114. Burd, C. G. & Emr, S. D. Phosphatidylinositol(3)-phosphate signaling mediated by specific binding to RING FYVE domains. Mol. Cell 2, 157-162 (1998). (Pubitemid 128378978)
115. Song, X. et al. Phox homology domains specifically bind phosphatidylinositol phosphates. Biochemistry 40, 8940-8944 (2001). (Pubitemid 32709527)
116. Ellson, C. D. et al. PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40phox. Nature Cell Biol. 3, 679-682 (2001).
117. 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).
118. Cheever, M. L. et al. Phox domain interaction with PtdIns(3)P targets the Vam7 t-SNARE to vacuole membranes. Nature Cell Biol. 3, 613-618 (2001).
119. Raiborg, C. et al. FYVE and coiled-coil domains determine the specific localisation of Hrs to early endosomes. J. Cell Sci. 114, 2255-2263 (2001). (Pubitemid 32633697)
120. Kihara, A., Noda, T., Ishihara, N. & Ohsumi, Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152, 519-530 (2001). (Pubitemid 34280235)
121. Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M. & Bilanges, B. The emerging mechanisms of isoform-specific PI3K signalling. Nature Rev. Mol. Cell. Biol. 11, 329-341 (2010).
122. Leevers, S. J., Weinkove, D., MacDougall, L. K., Hafen, E. & Waterfield, M. D. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 15, 6584-6594 (1996). (Pubitemid 26413791)
123. Chang, H. W. et al. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 276, 1848-1850 (1997). (Pubitemid 27443659)
124. Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation. Science 287, 1049-1053 (2000).
125. Sasaki, T. et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040-1046 (2000).
126. Li, Z. et al. Roles of PLC-β2 and-β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science 287, 1046-1049 (2000). (Pubitemid 30094361)
127. Okkenhaug, K. et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 1031-1034 (2002). (Pubitemid 34856039)
128. 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).
129. 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).
130. Foukas, L. C. et al. Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366-370 (2006). (Pubitemid 44050203)
131. Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell 125, 733-747 (2006).
132. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943-1947 (1997). (Pubitemid 27148818)
133. Steck, P. A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet. 15, 356-362 (1997). (Pubitemid 27147102)
134. Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet. 16, 64-67 (1997). (Pubitemid 27198157)
135. Marsh, D. J. et al. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nature Genet. 16, 333-334 (1997).
136. Maehama, T. & Dixon, J. E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 13375-13378 (1998).
137. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004). (Pubitemid 38541907)
138. Campbell, I. G. et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 64, 7678-7681 (2004). (Pubitemid 39446895)
139. 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). (Pubitemid 28062053)
140. Philp, A. J. et al. The phosphatidylinositol 3′-kinase p85α gene is an oncogene in human ovarian and colon tumors. Cancer Res. 61, 7426-7429 (2001). (Pubitemid 32995029)
141. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068 (2008).
142. Jaiswal, B. S. et al. Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell 16, 463-474 (2009).
143. Blondeau, F. et al. Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum. Mol. Genet. 9, 2223-2229 (2000).
144. Taylor, G. S., Maehama, T. & Dixon, J. E. Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc. Natl Acad. Sci. USA 97,8910-8915 (2000). (Pubitemid 30626647)
145. Bielas, S. L. et al. Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nature Genet. 41, 1032-1036 (2009).
146. Jacoby, M. et al. INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nature Genet. 41, 1027-1031 (2009).
147. Sadhu, C., Masinovsky, B., Dick, K., Sowell, C. G. & Staunton, D. E. Essential role of phosphoinositide 3-kinase δ in neutrophil directional movement. J. Immunol. 170, 2647-2654 (2003). (Pubitemid 36245657)
148. Camps, M. et al. Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nature Med. 11, 936-943 (2005). (Pubitemid 41294438)
149. Jackson, S. P. et al. PI 3-kinase p110β: a new target for antithrombotic therapy. Nature Med. 11, 507-514 (2005). (Pubitemid 40685973)
150. Walker, E. H., Perisic, O., Ried, C., Stephens, L. & Williams, R. L. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402, 313-320 (1999). (Pubitemid 129516270)
151. Huang, C. H. et al. The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations. Science 318, 1744-1748 (2007).
152. Zhang, X. et al. Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol. Cell 41, 567-578.
153. Berndt, A. et al. The p110 δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nature Chem. Biol. 6, 117-124.
154. Miller, S. et al. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327, 1638-1642 (2010).
155. Joly, M., Kazlauskas, A., Fay, F. S. & Corvera, S. Disruption of PDGF receptor trafficking by mutation of its PI-3 kinase binding sites. Science 263, 684-687 (1994). (Pubitemid 24076296)
156. Volinia, S. et al. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J. 14, 3339-3348 (1995).
157. Yao, R. & Cooper, G. M. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267, 2003-2006 (1995).
158. Scheid, M. P., Lauener, R. W. & Duronio, V. Role of phosphatidylinositol 3-OH-kinase activity in the inhibition of apoptosis in haemopoietic cells: phosphatidylinositol 3-OH-kinase inhibitors reveal a difference in signalling between interleukin-3 and granulocyte-macrophage colony stimulating factor. Biochem. J. 312, 159-162 (1995).
159. Vanhaesebroeck, B. et al. P110δ, a novel phosphoinositide 3-kinase in leukocytes. Proc. Natl Acad. Sci. USA 94, 4330-4335 (1997). (Pubitemid 27194241)
160. Chantry, D. et al. p110δ, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J. Biol. Chem. 272, 19236-19241 (1997). (Pubitemid 27337713)
161. Dudek, H. et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275, 661-665 (1997). (Pubitemid 27061332)
162. Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H. & Downward, J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16, 2783-2793 (1997). (Pubitemid 27226215)
163. Kauffmann-Zeh, A. et al. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 385, 544-548 (1997). (Pubitemid 27074674)
164. Kulik, G., Klippel, A. & Weber, M. J. Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol. Cell. Biol. 17, 1595-1606 (1997). (Pubitemid 27097389)
165. Kennedy, S. G. et al. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 11, 701-713 (1997). (Pubitemid 27157159)
166. Ahmed, N. N., Grimes, H. L., Bellacosa, A., Chan, T. O. & Tsichlis, P. N. Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc. Natl Acad. Sci. USA 94, 3627-3632 (1997). (Pubitemid 27180423)
167. Myers, M. P. et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc. Natl Acad. Sci. USA 95, 13513-13518 (1998). (Pubitemid 28523003)
168. Stauffer, T. P., Ahn, S. & Meyer, T. Receptor-induced transient reduction in plasma membrane PtdIns(4,5) P2 concentration monitored in living cells. Curr. Biol. 8, 343-346 (1998). (Pubitemid 28159121)
169. Fruman, D. A. et al. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85α. Science 283, 393-397 (1999).
170. Suzuki, H. et al. Xid-like immunodeficiency in mice with disruption of the p85α subunit of phosphoinositide 3-kinase. Science 283, 390-392 (1999).
171. 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). (Pubitemid 29070374)
172. 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).
173. Gewinner, C. et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16, 115-125 (2009).
174. Fedele, C. G. et al. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc. Natl Acad. Sc.i USA 107, 22231-2236 (2010).