Multiple roles for the p85α isoform in the regulation and function of PI3K signalling and receptor trafficking

Biochemical Journal

Volumn 441, Issue 1, 2012, Pages 23-37

  Mellor, Paul ^a,b   Furber, Levi A ^a   Nyarko, Jennifer N K ^a   Anderson, Deborah H ^a,b  

^a UNIVERSITY OF SASKATCHEWAN   (Canada)

^b SASKATCHEWAN CANCER AGENCY   (Canada)

Author keywords

Actin reorganization; Phosphatase and tensin homologue deleted on chromosome 10 (PTEN); Rab5 GTPase; Receptor degradation; Receptor endocytosis; Vesicle trafficking

Indexed keywords

ARGININE; CASPASE 8; CAVEOLIN; CLATHRIN; CYCLIC AMP DEPENDENT PROTEIN KINASE; INSULIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; PROTEIN P110; PROTEIN P58; PROTEIN P58 ALPHA; RAB PROTEIN; SERINE; TYROSINE; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; APOPTOSIS; BINDING SITE; CARCINOGENESIS; CELL FUSION; CELL MIGRATION; CELL PROLIFERATION; DIMERIZATION; ENDOCYTOSIS; ENDOSOME; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; IMMUNOPRECIPITATION; INSULIN RESISTANCE; MICROTUBULE ASSEMBLY; NEGATIVE FEEDBACK; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INDUCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; PROTEIN TRANSPORT; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; UBIQUITINATION;

ANIMALS; CLASS IA PHOSPHATIDYLINOSITOL 3-KINASE; GENE EXPRESSION REGULATION; HUMANS; PROTEIN ISOFORMS; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION;

EID: 84055214006     PISSN: 02646021     EISSN: 14708728     Source Type: Journal    
DOI: 10.1042/BJ20111164     Document Type: Review

References (213)

1. Fruman, D. A. (2010) Regulatory subunits of class IA PI3K. Curr. Top. Microbiol. Immunol. 346, 225-244
2. Kok, K., Geering, B. and Vanhaesebroeck, B. (2009) Regulation of phosphoinositide 3-kinase expression in health and disease. Trends Biochem. Sci. 34, 115-127
3. Yu, J., Zhang, Y., McIlroy, J., Rordorf-Nikolic, T., Orr, G. A. and Backer, J. M. (1998) Regulation of the p85/p110 phosphatidylinositol 3′-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Mol. Cell. Biol. 18, 1379-1387 (Pubitemid 28100902)
4. Liu, P., Cheng, H., Roberts, T. M. and Zhao, J. J. (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discovery 8, 627-644
5. Cantley, L. C. (2002) The phosphoinositide 3-kinase pathway. Science 296, 1655-1657
6. Yenush, L., Zanella, C., Uchida, T., Bernal, D. and White, M. F. (1998) The pleckstrin homology and phosphotyrosine binding domains of insulin receptor substrate 1 mediate inhibition of apoptosis by insulin. Mol. Cell. Biol. 18, 6784-6794 (Pubitemid 28500566)
7. Taniguchi, C. M., Emanuelli, B. and Kahn, C. R. (2006) Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85-96 (Pubitemid 43278292)
8. Miled, N., Yan, Y., Hon, W. C., Perisic, O., Zvelebil, M., Inbar, Y., Schneidman-Duhovny, D., Wolfson, H. J., Backer, J. M. and Williams, R. L. (2007) Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317, 239-242 (Pubitemid 47076198)
9. Rodriguez-Viciana, P., Warne, P. H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M. J., Waterfield, M. D. and Downward, J. (1994) Phosphatidylinositol- 3-OH kinase as a direct target of Ras. Nature 370, 527-532 (Pubitemid 24264918)
10. Rodriguez-Viciana, P., Warne, P. H., Vanhaesebroeck, B., Waterfield, M. D. and Downward, J. (1996) Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J. 15, 2442-2451 (Pubitemid 26151184)
11. Castellano, E. and Downward, J. (2010) Role of RAS in the regulation of PI 3-kinase. Curr. Top. Microbiol. Immunol. 346, 143-169
12. Toker, A. and Cantley, L. C. (1997) Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387, 673-676 (Pubitemid 27270600)
13. Stephens, L., Anderson, K., Stokoe, D., Erdjument-Bromage, H., Painter, G. F., Holmes, A. B., Gaffney, P. R., Reese, C. B., McCormick, F., Tempst, P. et al. (1998) Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279, 710-714 (Pubitemid 28144551)
14. Alessi, D. R., James, S. R., Downes, C. P., Holmes, A. B., Gaffney, P. R., Reese, C. B. and Cohen, P. (1997) Characterization of a 3-phosphoinositide- dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr. Biol. 7, 261-269 (Pubitemid 27176852)
15. Vasudevan, K. M. and Garraway, L. A. (2010) AKT signaling in physiology and disease. Curr. Top. Microbiol. Immunol. 347, 105-133
16. Fayard, E., Xue, G., Parcellier, A., Bozulic, L. and Hemmings, B. A. (2010) Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. Curr. Top. Microbiol. Immunol. 346, 31-56
17. Carnero, A. (2010) The PKB/AKT pathway in cancer. Curr. Pharm. Des. 16, 34-44
18. Carracedo, A. and Pandolfi, P. P. (2008) The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 27, 5527-5541
19. Saarikangas, J., Zhao, H. and Lappalainen, P. (2010) Regulation of the actin cytoskeleton-plasma membrane interplay by phosphoinositides. Physiol. Rev. 90, 259-289
20. Sever, S., Muhlberg, A. B. and Schmid, S. L. (1999) Impairment of dynamin's GAP domain stimulates receptor-mediated endocytosis. Nature 398, 481-486
21. Sweitzer, S. M. and Hinshaw, J. E. (1998) Dynamin undergoes a GTP-dependent conformational change causing vesiculation. Cell 93, 1021-1029 (Pubitemid 28280795)
22. Doherty, G. J. and McMahon, H. T. (2009) Mechanisms of endocytosis. Annu. Rev. Biochem. 78, 857-902
23. Galletta, B. J., Mooren, O. L. and Cooper, J. A. (2010) Actin dynamics and endocytosis in yeast and mammals. Curr. Opin. Biotechnol. 21, 604-610
24. Costa, C., Germena, G. and Hirsch, E. (2010) Dissection of the interplay between class I PI3Ks and Rac signaling in phagocytic functions. ScientificWorldJournal 10, 1826-1839
25. Ehrhardt, C. and Ludwig, S. (2009) A new player in a deadly game: influenza viruses and the PI3K/Akt signalling pathway. Cell. Microbiol. 11, 863-871
26. Dhand, R., Hiles, I., Panayotou, G., Roche, S., Fry, M. J., Gout, I., Totty, N. F., Truong, O., Vicendo, P., Yonezawa, K. et al. (1994) PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J. 13, 522-533 (Pubitemid 24050666)
27. Yoshizaki, T., Maegawa, H., Egawa, K., Ugi, S., Nishio, Y., Imamura, T., Kobayashi, T., Tamura, S., Olefsky, J. M. and Kashiwagi, A. (2004) Protein phosphatase-2Cα as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. J. Biol. Chem. 279, 22715-22726 (Pubitemid 38679472)
28. Cosentino, C., Di Domenico, M., Porcellini, A., Cuozzo, C., De Gregorio, G., Santillo, M. R., Agnese, S., Di Stasio, R., Feliciello, A., Migliaccio, A. and Avvedimento, E. V. (2007) p85 regulatory subunit of PI3K mediates cAMP-PKA and estrogens biological effects on growth and survival. Oncogene 26, 2095-2103 (Pubitemid 46514751)
29. De Gregorio, G., Coppa, A., Cosentino, C., Ucci, S., Messina, S., Nicolussi, A., D'Inzeo, S., Di Pardo, A., Avvedimento, E. V. and Porcellini, A. (2007) The p85 regulatory subunit of PI3K mediates TSH-cAMP-PKA growth and survival signals. Oncogene 26, 2039-2047 (Pubitemid 46514747)
30. von Willebrand, M., Williams, S., Saxena, M., Gilman, J., Tailor, P., Jascur, T., Amarante-Mendes, G. P., Green, D. R. and Mustelin, T. (1998) Modification of phosphatidylinositol 3-kinase SH2 domain binding properties by Abl- or Lck-mediated tyrosine phosphorylation at Tyr-688. J. Biol. Chem. 273, 3994-4000 (Pubitemid 28103262)
31. Cuevas, B. D., Lu, Y., Mao, M., Zhang, J., LaPushin, R., Siminovitch, K. and Mills, G. B. (2001) Tyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase. J. Biol. Chem. 276, 27455-27461
32. Farias, E. F., Marzan, C. and Mira-y-Lopez, R. (2005) Cellular retinol-binding protein-I inhibits PI3K/Akt signaling through a retinoic acid receptor-dependent mechanism that regulates p85-p110 heterodimerization. Oncogene 24, 1598-1606 (Pubitemid 40396089)
33. Kavanaugh, W. M., Turck, C. W., Klippel, A. and Williams, L. T. (1994) Tyrosine 508 of the 85-kilodalton subunit of phosphatidylinositol 3-kinase is phosphorylated by the platelet-derived growth factor receptor. Biochemistry 33, 11046-11050 (Pubitemid 24296361)
34. Chodniewicz, D. and Zhelev, D. V. (2003) Novel pathways of F-actin polymerization in the human neutrophil. Blood 102, 2251-2258 (Pubitemid 37122407)
35. Tsuboi, N., Utsunomiya, T., Roberts, R. L., Ito, H., Takahashi, K., Noda, M. and Takahashi, T. (2008) The tyrosine phosphatase CD148 interacts with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem. J. 413, 193-200 (Pubitemid 351946875)
36. Fang, D., Wang, H. Y., Fang, N., Altman, Y., Elly, C. and Liu, Y. C. (2001) Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J. Biol. Chem. 276, 4872-4878
37. Fang, D. and Liu, Y. C. (2001) Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat. Immunol. 2, 870-875
38. Han, J., Luby-Phelps, K., Das, B., Shu, X., Xia, Y., Mosteller, R. D., Krishna, U. M., Falck, J. R., White, M. A. and Broek, D. (1998) Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science 279, 558-560 (Pubitemid 28067283)
39. Ma, A. D., Metjian, A., Bagrodia, S., Taylor, S. and Abrams, C. S. (1998) Cytoskeletal reorganization by G protein-coupled receptors is dependent on phosphoinositide 3-kinase γ, a Rac guanosine exchange factor, and Rac. Mol. Cell. Biol. 18, 4744-4751 (Pubitemid 28343059)
40. Yu, J., Wjasow, C. and Backer, J. M. (1998) Regulation of the p85/p110αphosphatidylinositol 3′-kinase. Distinct roles for the N-terminal and C-terminal SH2 domains. J. Biol. Chem. 273, 30199-30203 (Pubitemid 28545483)
41. Kapeller, R., Toker, A., Cantley, L. C. and Carpenter, C. L. (1995) Phosphoinositide 3-kinase binds constitutively to α/β-tubulin and binds to γ-tubulin in response to insulin. J. Biol. Chem. 270, 25985-25991
42. Sun, X. J., Rothenberg, P., Kahn, C. R., Backer, J. M., Araki, E., Wilden, P. A., Cahill, D. A., Goldstein, B. J. and White, M. F. (1991) Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352, 73-77 (Pubitemid 21896701)
43. Sattler, M., Mohi, M. G., Pride, Y. B., Quinnan, L. R., Malouf, N. A., Podar, K., Gesbert, F., Iwasaki, H., Li, S., Van Etten, R. A. et al. (2002) Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell 1, 479-492 (Pubitemid 41039128)
44. Harrison-Findik, D., Susa, M. and Varticovski, L. (1995) Association of phosphatidylinositol 3-kinase with SHC in chronic myelogeneous leukemia cells. Oncogene 10, 1385-1391
45. Gu, H., Maeda, H., Moon, J. J., Lord, J. D., Yoakim, M., Nelson, B. H. and Neel, B. G. (2000) New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. Mol. Cell. Biol. 20, 7109-7120
46. Sattler, M., Salgia, R., Okuda, K., Uemura, N., Durstin, M. A., Pisick, E., Xu, G., Li, J. L., Prasad, K. V. and Griffin, J. D. (1996) The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR/ABL and p210BCR/ABL to the phosphatidylinositol-3′ kinase pathway. Oncogene 12, 839-846
47. Woodfield, R. J., Hodgkin, M. N., Akhtar, N., Morse, M. A., Fuller, K. J., Saqib, K., Thompson, N. T. and Wakelam, M. J. (2001) The p85 subunit of phosphoinositide 3-kinase is associated with beta-catenin in the cadherin-based adhesion complex. Biochem. J. 360, 335-344 (Pubitemid 33151328)
48. Torres, V. A., Mielgo, A., Barila, D., Anderson, D. H. and Stupack, D. (2008) Caspase 8 promotes peripheral localization and activation of Rab5. J. Biol. Chem. 283, 36280-36289
49. King, T. R., Fang, Y., Mahon, E. S. and Anderson, D. H. (2000) Using a phage display library to identify basic residues in A-Raf required to mediate binding to the Src homology 2 domains of the p85 subunit of phosphatidylinositol 3′-kinase. J. Biol. Chem. 275, 36450-36456
50. Fang, Y., Johnson, L. M., Mahon, E. S. and Anderson, D. H. (2002) Two phosphorylation-independent sites on the p85 SH2 domains bind A-Raf kinase. Biochem. Biophys. Res. Commun. 290, 1267-1274 (Pubitemid 34694442)
51. Mahon, E. S., Hawrysh, A. D., Chagpar, R. B., Johnson, L. M. and Anderson, D. H. (2005) A-Raf associates with and regulates platelet-derived growth factor receptor signalling. Cell. Signalling 17, 857-868 (Pubitemid 40353656)
52. Ignatiuk, A., Quickfall, J. P., Hawrysh, A. D., Chamberlain, M. D. and Anderson, D. H. (2006) The smaller isoforms of ankyrin 3 bind to the p85 subunit of phosphatidylinositol 3′-kinase and enhance platelet-derived growth factor receptor down-regulation. J. Biol. Chem. 281, 5956-5964 (Pubitemid 43847696)
53. Harpur, A. G., Layton, M. J., Das, P., Bottomley, M. J., Panayotou, G., Driscoll, P. C. and Waterfield, M. D. (1999) Intermolecular interactions of the p85α regulatory subunit of phosphatidylinositol 3-kinase. J. Biol. Chem. 274, 12323-12332
54. Brachmann, S. M., Ueki, K., Engelman, J. A., Kahn, R. C. and Cantley, L. C. (2005) Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol. Cell. Biol. 25, 1596-1607 (Pubitemid 40282598)
55. Geering, B., Cutillas, P. R., Nock, G., Gharbi, S. I. and Vanhaesebroeck, B. (2007) Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc. Natl. Acad. Sci. U.S.A. 104, 7809-7814 (Pubitemid 47185833)
56. Bandyopadhyay, G. K., Yu, J. G., Ofrecio, J. and Olefsky, J. M. (2005) Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54, 2351-2359 (Pubitemid 41134262)
57. Barbour, L. A., Mizanoor Rahman, S., Gurevich, I., Leitner, J. W., Fischer, S. J., Roper, M. D., Knotts, T. A., Vo, Y., McCurdy, C. E., Yakar, S. et al. (2005) Increased p85α is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess. J. Biol. Chem. 280, 37489-37494 (Pubitemid 41642357)
58. Barbour, L. A., Shao, J., Qiao, L., Leitner, W., Anderson, M., Friedman, J. E. and Draznin, B. (2004) Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. Endocrinology 145, 1144-1150 (Pubitemid 38280994)
59. del Rincon, J. P., Iida, K., Gaylinn, B. D., McCurdy, C. E., Leitner, J. W., Barbour, L. A., Kopchick, J. J., Friedman, J. E., Draznin, B. and Thorner, M. O. (2007) Growth hormone regulation of p85α expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes 56, 1638-1646 (Pubitemid 46842597)
60. Musacchio, A., Cantley, L. C. and Harrison, S. C. (1996) Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85αsubunit. Proc. Natl. Acad. Sci. U.S.A. 93, 14373-14378 (Pubitemid 26418973)
61. Park, S. W., Zhou, Y., Lee, J., Lu, A., Sun, C., Chung, J., Ueki, K. and Ozcan, U. (2010) The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocation. Nat. Med. 16, 429-437
62. Batra-Safferling, R., Granzin, J., Modder, S., Hoffmann, S. and Willbold, D. (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
63. Guinebault, C., Payrastre, B., Racaud-Sultan, C., Mazarguil, H., Breton, M., Mauco, G., Plantavid, M. and Chap, H. (1995) Integrin-dependent translocation of phosphoinositide 3-kinase to the cytoskeleton of thrombin-activated platelets involves specific interactions of p85α with actin filaments and focal adhesion kinase. J. Cell Biol. 129, 831-842
64. Li, E., Stupack, D. G., Brown, S. L., Klemke, R., Schlaepfer, D. D. and Nemerow, G. R. (2000) Association of p130CAS with phosphatidylinositol-3-OH kinase mediates adenovirus cell entry. J. Biol. Chem. 275, 14729-14735 (Pubitemid 30339766)
65. Maddika, S., Wiechec, E., Ande, S. R., Poon, I. K., Fischer, U., Wesselborg, S., Jans, D. A., Schulze-Osthoff, K. and Los, M. (2008) Interaction with PI3-kinase contributes to the cytotoxic activity of apoptin. Oncogene 27, 3060-3065 (Pubitemid 351668005)
66. Gout, I., Middleton, G., Adu, J., Ninkina, N. N., Drobot, L. B., Filonenko, V., Matsuka, G., Davies, A. M., Waterfield, M. and Buchman, V. L. (2000) Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein. EMBO J. 19, 4015-4025 (Pubitemid 30608540)
67. Badour, K., McGavin, M. K., Zhang, J., Freeman, S., Vieira, C., Filipp, D., Julius, M., Mills, G. B. and Siminovitch, K. A. (2007) Interaction of the Wiskott-Aldrich syndrome protein with sorting nexin 9 is required for CD28 endocytosis and cosignaling in T cells. Proc. Natl. Acad. Sci. U.S.A. 104, 1593-1598 (Pubitemid 46214635)
68. Ren, S. Y., Bolton, E., Mohi, M. G., Morrione, A., Neel, B. G. and Skorski, T. (2005) Phosphatidylinositol 3-kinase p85α subunit-dependent interaction with BCR/ABL-related fusion tyrosine kinases: molecular mechanisms and biological consequences. Mol. Cell. Biol. 25, 8001-8008 (Pubitemid 41262994)
69. Gout, I., Dhand, R., Hiles, I. D., Fry, M. J., Panayotou, G., Das, P., Truong, O., Totty, N. F., Hsuan, J., Booker, G. W. et al. (1993) The GTPase dynamin binds to and is activated by a subset of SH3 domains. Cell 75, 25-36 (Pubitemid 23306018)
70. Scaife, R., Gout, I., Waterfield, M. D. and Margolis, R. L. (1994) Growth factor-induced binding of dynamin to signal transduction proteins involves sorting to distinct and separate proline-rich dynamin sequences. EMBO J. 13, 2574-2582 (Pubitemid 24188390)
71. Dombrosky-Ferlan, P. M. and Corey, S. J. (1997) Yeast two-hybrid in vivo association of the Src kinase Lyn with the proto-oncogene product Cbl but not with the p85 subunit of PI 3-kinase. Oncogene 14, 2019-2024 (Pubitemid 27237004)
72. Lundmark, R. and Carlsson, S. R. (2009) SNX9: a prelude to vesicle release. J. Cell Sci. 122, 5-11
73. Wang, J., Auger, K. R., Jarvis, L., Shi, Y. and Roberts, T. M. (1995) Direct association of Grb2 with the p85 subunit of phosphatidylinositol 3-kinase. J. Biol. Chem. 270, 12774-12780
74. Weinger, J. G., Gohari, P., Yan, Y., Backer, J. M., Varnum, B. and Shafit-Zagardo, B. (2008) In brain, Axl recruits Grb2 and the p85 regulatory subunit of PI3 kinase; in vitro mutagenesis defines the requisite binding sites for downstream Akt activation. J. Neurochem. 106, 134-146 (Pubitemid 351840196)
75. Gelkop, S., Babichev, Y. and Isakov, N. (2001) T cell activation induces direct binding of the Crk adapter protein to the regulatory subunit of phosphatidylinositol 3-kinase (p85) via a complex mechanism involving the Cbl protein. J. Biol. Chem. 276, 36174-36182
76. Shibasaki, F., Fukami, K., Fukui, Y. and Takenawa, T. (1994) Phosphatidylinositol 3-kinase binds to α-actinin through the p85 subunit. Biochem. J. 302, 551-557 (Pubitemid 24280112)
77. Liu, X., Marengere, L. E., Koch, C. A. and Pawson, T. (1993) The v-Src SH3 domain binds phosphatidylinositol 3′-kinase. Mol. Cell. Biol. 13, 5225-5232 (Pubitemid 23260627)
78. Prasad, K. V., Janssen, O., Kapeller, R., Raab, M., Cantley, L. C. and Rudd, C. E. (1993) Src-homology 3 domain of protein kinase p59fyn mediates binding to phosphatidylinositol 3-kinase in T cells. Proc. Natl. Acad. Sci. U.S.A. 90, 7366-7370 (Pubitemid 23222451)
79. Kapeller, R., Prasad, K. V., Janssen, O., Hou, W., Schaffhausen, B. S., Rudd, C. E. and Cantley, L. C. (1994) Identification of two SH3-binding motifs in the regulatory subunit of phosphatidylinositol 3-kinase. J. Biol. Chem. 269, 1927-1933
80. Pleiman, C. M., Hertz, W. M. and Cambier, J. C. (1994) Activation of phosphatidylinositol-3′ kinase by Src-family kinase SH3 binding to the p85 subunit. Science 263, 1609-1612
81. Heasman, S. J. and Ridley, A. J. (2008) Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat. Rev. Mol. Cell Biol. 9, 690-701
82. Zheng, Y., Bagrodia, S. and Cerione, R. A. (1994) Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85. J. Biol. Chem. 269, 18727-18730 (Pubitemid 24226178)
83. Bokoch, G. M., Vlahos, C. J., Wang, Y., Knaus, U. G. and Traynor-Kaplan, A. E. (1996) Rac GTPase interacts specifically with phosphatidylinositol 3-kinase. Biochem. J. 315, 775-779 (Pubitemid 26147602)
84. Chamberlain, M. D., Berry, T. R., Pastor, M. C. and Anderson, D. H. (2004) The p85α subunit of phosphatidylinositol 3′-kinase binds to and stimulates the GTPase activity of Rab proteins. J. Biol. Chem. 279, 48607-48614 (Pubitemid 39625735)
85. Fidyk, N. J. and Cerione, R. A. (2002) Understanding the catalytic mechanism of GTPase-activating proteins: demonstration of the importance of switch domain stabilization in the stimulation of GTP hydrolysis. Biochemistry 41, 15644-15653 (Pubitemid 36062469)
86. Kang, H., Schneider, H. and Rudd, C. E. (2002) Phosphatidylinositol 3-kinase p85 adaptor function in T-cells. Co-stimulation and regulation of cytokine transcription independent of associated p110. J. Biol. Chem. 277, 912-921 (Pubitemid 34968834)
87. Garcia, Z., Silio, V., Marques, M., Cortes, I., Kumar, A., Hernandez, C., Checa, A. I., Serrano, A. and Carrera, A. C. (2006) A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis. EMBO J. 25, 4740-4751 (Pubitemid 44607020)
88. Harris, K. P. and Tepass, U. (2010) Cdc42 and vesicle trafficking in polarized cells. Traffic 11, 1272-1279
89. Chamberlain, M. D., Oberg, J. C., Furber, L. A., Poland, S. F., Hawrysh, A. D., Knafelc, S. M., McBride, H. M. and Anderson, D. H. (2010) Deregulation of Rab5 and Rab4 proteins in p85R274A-expressing cells alters PDGFR trafficking. Cell. Signalling 22, 1562-1575
90. Mitra, S., Cheng, K. W. and Mills, G. B. (2011) Rab GTPases implicated in inherited and acquired disorders. Semin. Cell Dev. Biol. 22, 57-68
91. Hutagalung, A. H. and Novick, P. J. (2011) Role of Rab GTPases in membrane traffic and cell physiology. Physiol. Rev. 91, 119-149
92. Stenmark, H. (2009) Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 10, 513-525
93. Chagpar, R. B., Links, P. H., Pastor, M. C., Furber, L. A., Hawrysh, A. D., Chamberlain, M. D. and Anderson, D. H. (2010) Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase. Proc. Natl. Acad. Sci. U.S.A. 107, 5471-5476
94. Anderson, D. H. (2010) p85 plays a critical role in controlling flux through the PI3K/PTEN signaling axis through dual regulation of both p110 (PI3K) and PTEN. Cell Cycle 9, 2055-2056
95. Vanhaesebroeck, B., Leevers, S. J., Ahmadi, K., Timms, J., Katso, R., Driscoll, P. C., Woscholski, R., Parker, P. J. and Waterfield, M. D. (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 70, 535-602 (Pubitemid 32662219)
96. Maier, U., Babich, A. and Nurnberg, B. (1999) Roles of non-catalytic subunits in Gβγ-induced activation of class I phosphoinositide 3-kinase isoforms β and γ. J. Biol. Chem. 274, 29311-29317
97. Hirsch, E., Braccini, L., Ciraolo, E., Morello, F. and Perino, A. (2009) Twice upon a time: PI3K's secret double life exposed. Trends Biochem. Sci. 34, 244-248
98. Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M. and Bilanges, B. (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol. 11, 329-341
99. Chantry, D., Vojtek, A., Kashishian, A., Holtzman, D. A., Wood, C., Gray, P. W., Cooper, J. A. and Hoekstra, M. F. (1997) p110δ, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J. Biol. Chem. 272, 19236-19241 (Pubitemid 27337713)
100. Zhao, L. and Vogt, P. K. (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27, 5486-5496
101. MacDougall, L. K., Domin, J. and Waterfield, M. D. (1995) A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction. Curr. Biol. 5, 1404-1415 (Pubitemid 3008923)
102. Arcaro, A., Volinia, S., Zvelebil, M. J., Stein, R., Watton, S. J., Layton, M. J., Gout, I., Ahmadi, K., Downward, J. and Waterfield, M. D. (1998) Human phosphoinositide 3-kinase C2β, the role of calcium and the C2 domain in enzyme activity. J. Biol. Chem. 273, 33082-33090 (Pubitemid 28557705)
103. Brown, R. A., Domin, J., Arcaro, A., Waterfield, M. D. and Shepherd, P. R. (1999) Insulin activates the α isoform of class II phosphoinositide 3-kinase. J. Biol. Chem. 274, 14529-14532
104. Backer, J. M. (2008) The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem. J. 410, 1-17
105. Huang, C. H., Mandelker, D., Schmidt-Kittler, O., Samuels, Y., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., Gabelli, S. B. and Amzel, L. M. (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kα mutations. Science 318, 1744-1748 (Pubitemid 350274378)
106. Zhang, X., Vadas, O., Perisic, O., Anderson, K. E., Clark, J., Hawkins, P. T., Stephens, L. R. and Williams, R. L. (2010) Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol. Cell 41, 567-578
107. Castellano, E. and Downward, J. (2011) RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2, 261-274
108. Gupta, S., Ramjaun, A. R., Haiko, P., Wang, Y., Warne, P. H., Nicke, B., Nye, E., Stamp, G., Alitalo, K. and Downward, J. (2007) Binding of ras to phosphoinositide 3-kinase p110α is required for ras-driven tumorigenesis in mice. Cell 129, 957-968 (Pubitemid 46802703)
109. Gabelli, S. B., Huang, C. H., Mandelker, D., Schmidt-Kittler, O., Vogelstein, B. and Amzel, L. M. (2010) Structural effects of oncogenic PI3Kα mutations. Curr. Top. Microbiol. Immunol. 347, 43-53
110. Vogt, P. K., Hart, J. R., Gymnopoulos, M., Jiang, H., Kang, S., Bader, A. G., Zhao, L. and Denley, A. (2010) Phosphatidylinositol 3-kinase: the oncoprotein. Curr. Top. Microbiol. Immunol. 347, 79-104
111. Backer, J. M. (2010) The regulation of class IA PI 3-kinases by inter-subunit interactions. Curr. Top. Microbiol. Immunol. 346, 87-114
112. Samuels, Y. and Waldman, T. (2010) Oncogenic mutations of PIK3CA in human cancers. Curr. Top. Microbiol. Immunol. 347, 21-41
113. Wong, K. K., Engelman, J. A. and Cantley, L. C. (2010) Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev. 20, 87-90
114. Costa, C. and Hirsch, E. (2010) More than just kinases: the scaffolding function of PI3K. Curr. Top. Microbiol. Immunol. 346, 171-181
115. Ikenoue, T., Kanai, F., Hikiba, Y., Obata, T., Tanaka, Y., Imamura, J., Ohta, M., Jazag, A., Guleng, B., Tateishi, K. et al. (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res. 65, 4562-4567 (Pubitemid 40740791)
116. Samuels, Y. and Velculescu, V. E. (2004) Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3, 1221-1224 (Pubitemid 40268595)
117. Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Gazdar, A., Powell, S. M., Riggins, G. J. et al. (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (Pubitemid 38541907)
118. Zhao, J. J., Cheng, H., Jia, S., Wang, L., Gjoerup, O. V., Mikami, A. and Roberts, T. M. (2006) The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc. Natl. Acad. Sci. U.S.A. 103, 16296-16300 (Pubitemid 44715190)
119. Knobbe, C. B., Trampe-Kieslich, A. and Reifenberger, G. (2005) Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathol. Appl. Neurobiol. 31, 486-490 (Pubitemid 41337782)
120. Hickey, F. B. and Cotter, T. G. (2006) BCR-ABL regulates phosphatidylinositol 3-kinase-p110γ transcription and activation and is required for proliferation and drug resistance. J. Biol. Chem. 281, 2441-2450 (Pubitemid 43845703)
121. An, H. J., Cho, N. H., Yang, H. S., Kwak, K. B., Kim, N. K., Oh, D. Y., Lee, S. W., Kim, H. O. and Koh, J. J. (2007) Targeted RNA interference of phosphatidylinositol 3-kinase p110β induces apoptosis and proliferation arrest in endometrial carcinoma cells. J. Pathol. 212, 161-169 (Pubitemid 46852094)
122. Benistant, C., Chapuis, H. and Roche, S. (2000) A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110β) in de novo DNA synthesis of human colon carcinoma cells. Oncogene 19, 5083-5090
123. Denley, A., Gymnopoulos, M., Hart, J. R., Jiang, H., Zhao, L. and Vogt, P. K. (2008) Biochemical and biological characterization of tumor-associated mutations of p110α. Methods Enzymol. 438, 291-305
124. Sujobert, P., Bardet, V., Cornillet-Lefebvre, P., Hayflick, J. S., Prie, N., Verdier, F., Vanhaesebroeck, B., Muller, O., Pesce, F., Ifrah, N. et al. (2005) Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106, 1063-1066 (Pubitemid 41076455)
125. Mandelker, D., Gabelli, S. B., Schmidt-Kittler, O., Zhu, J., Cheong, I., Huang, C. H., Kinzler, K. W., Vogelstein, B. and Amzel, L. M. (2009) A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane. Proc. Natl. Acad. Sci. U.S.A. 106, 16996-17001
126. Parsons, D. W., Jones, S., Zhang, X., Lin, J. C., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I. M., Gallia, G. L. et al. (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-1812
127. Wood, L. D., Parsons, D. W., Jones, S., Lin, J., Sjoblom, T., Leary, R. J., Shen, D., Boca, S. M., Barber, T., Ptak, J. et al. (2007) The genomic landscapes of human breast and colorectal cancers. Science 318, 1108-1113 (Pubitemid 350134889)
128. Philp, A. J., Campbell, I. G., Leet, C., Vincan, E., Rockman, S. P., Whitehead, R. H., Thomas, R. J. and Phillips, W. A. (2001) The phosphatidylinositol 3′-kinase p85α gene is an oncogene in human ovarian and colon tumors. Cancer Res. 61, 7426-7429 (Pubitemid 32995029)
129. Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B. et al. (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069-1075
130. Jones, S., Zhang, X., Parsons, D. W., Lin, J. C., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., Jimeno, A. et al. (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801-1806
131. Jaiswal, B. S., Janakiraman, V., Kljavin, N. M., Chaudhuri, S., Stern, H. M., Wang, W., Kan, Z., Dbouk, H. A., Peters, B. A., Waring, P. et al. (2009) Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell 16, 463-474
132. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068
133. Dbouk, H. A., Pang, H., Fiser, A. and Backer, J. M. (2010) A biochemical mechanism for the oncogenic potential of the p110β catalytic subunit of phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. U.S.A. 107, 19897-19902
134. Sun, M., Hillmann, P., Hofmann, B. T., Hart, J. R. and Vogt, P. K. (2010) Cancer-derived mutations in the regulatory subunit p85α of phosphoinositide 3-kinase function through the catalytic subunit p110α. Proc. Natl. Acad. Sci. U.S.A. 107, 15547-15552
135. Chalhoub, N., Baker, S. J., Chalhoub, N. and Baker, S. J. (2009) PTEN and the PI3-kinase pathway in cancer. Annu. Rev. Pathol. 4, 127-150
136. Salmena, L., Carracedo, A., Pandolfi, P. P., Salmena, L., Carracedo, A. and Pandolfi, P. P. (2008) Tenets of PTEN tumor suppression. Cell 133, 403-414 (Pubitemid 351622014)
137. Planchon, S. M., Waite, K. A., Eng, C., Planchon, S. M., Waite, K. A. and Eng, C. (2008) The nuclear affairs of PTEN. J. Cell Sci. 121, 249-253 (Pubitemid 351356695)
138. Berger, A. H., Pandolfi, P. P., Berger, A. H. and Pandolfi, P. P. (2011) Haplo-insufficiency: a driving force in cancer. J. Pathol. 223, 137-146
139. Carracedo, A., Alimonti, A. and Pandolfi, P. (2011) PTEN level in tumor sppression: how much is too little? Cancer Res. 71, 629-633
140. Di Cristofano, A., Pesce, B., Cordon-Cardo, C. and Pandolfi, P. P. (1998) Pten is essential for embryonic development and tumour suppression. Nat. Genet. 19, 348-355 (Pubitemid 28357906)
141. Podsypanina, K., Ellenson, L. H., Nemes, A., Gu, J., Tamura, M., Yamada, K. M., Cordon-Cardo, C., Catoretti, G., Fisher, P. E. and Parsons, R. (1999) Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl. Acad. Sci. U.S.A. 96, 1563-1568 (Pubitemid 29098491)
142. Stambolic, V., Tsao, M. S., Macpherson, D., Suzuki, A., Chapman, W. B. and Mak, T. W. (2000) High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in Pten+/- mice. Cancer Res. 60, 3605-3611 (Pubitemid 30482183)
143. Luchman, H. A., Benediktsson, H., Villemaire, M. L., Peterson, A. C. and Jirik, F. R. (2008) The pace of prostatic intraepithelial neoplasia development is determined by the timing of Pten tumor suppressor gene excision. PLoS ONE 3, e3940
144. Ratnacaram, C. K., Teletin, M., Jiang, M., Meng, X., Chambon, P. and Metzger, D. (2008) Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma. Proc. Natl. Acad. Sci. U.S.A. 105, 2521-2526 (Pubitemid 351520546)
145. Chen, Z., Trotman, L. C., Shaffer, D., Lin, H. K., Dotan, Z. A., Niki, M., Koutcher, J. A., Scher, H. I., Ludwig, T., Gerald, W. et al. (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725-730 (Pubitemid 41117277)
146. Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C. and Pandolfi, P. P. (2001) Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat. Genet. 27, 222-224
147. Alimonti, A., Carracedo, A., Clohessy, J. G., Trotman, L. C., Nardella, C., Egia, A., Salmena, L., Sampieri, K., Haveman, W. J., Brogi, E. et al. (2010) Subtle variations in Pten dose determine cancer susceptibility. Nat. Genet. 42, 454-458
148. Trotman, L. C., Niki, M., Dotan, Z. A., Koutcher, J. A., Di Cristofano, A., Xiao, A., Khoo, A. S., Roy-Burman, P., Greenberg, N. M., Van Dyke, T. et al. (2003) Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, e59
149. Fruman, D. A., Mauvais-Jarvis, F., Pollard, D. A., Yballe, C. M., Brazil, D., Bronson, R. T., Kahn, C. R. and Cantley, L. C. (2000) Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α. Nat. Genet. 26, 379-382
150. Terauchi, Y., Tsuji, Y., Satoh, S., Minoura, H., Murakami, K., Okuno, A., Inukai, K., Asano, T., Kaburagi, Y., Ueki, K. et al. (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85αa subunit of phosphoinositide 3-kinase. Nat. Genet. 21, 230-235 (Pubitemid 29070374)
151. Bi, L., Okabe, I., Bernard, D. J., Wynshaw-Boris, A. and Nussbaum, R. L. (1999) 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
152. Bi, L., Okabe, I., Bernard, D. J. and Nussbaum, R. L. (2002) Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase. Mamm. Genome 13, 169-172 (Pubitemid 34185317)
153. Foukas, L. C., Claret, M., Pearce, W., Okkenhaug, K., Meek, S., Peskett, E., Sancho, S., Smith, A. J., Withers, D. J. and Vanhaesebroeck, B. (2006) Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366-370 (Pubitemid 44050203)
154. Wong, J. T., Kim, P. T., Peacock, J. W., Yau, T. Y., Mui, A. L., Chung, S. W., Sossi, V., Doudet, D., Green, D., Ruth, T. J. et al. (2007) Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity. Diabetologia 50, 395-403 (Pubitemid 46169771)
155. Mauvais-Jarvis, F., Ueki, K., Fruman, D. A., Hirshman, M. F., Sakamoto, K., Goodyear, L. J., Iannacone, M., Accili, D., Cantley, L. C., Kahn, C. R. et al. (2002) Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J. Clin. Invest. 109, 141-149 (Pubitemid 34052550)
156. Ueki, K., Fruman, D. A., Brachmann, S. M., Tseng, Y. H., Cantley, L. C. and Kahn, C. R. (2002) Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol. Cell. Biol. 22, 965-977 (Pubitemid 34053073)
157. Luo, J. and Cantley, L. C. (2005) The negative regulation of phosphoinositide 3-kinase signaling by p85 and it's implication in cancer. Cell Cycle 4, 1309-1312 (Pubitemid 41437108)
158. Barber, D. F., Alvarado-Kristensson, M., Gonzalez-Garcia, A., Pulido, R. and Carrera, A. C. (2006) PTEN regulation, a novel function for the p85 subunit of phosphoinositide 3-kinase. Sci. STKE 2006, pe49
159. Luo, J., Field, S. J., Lee, J. Y., Engelman, J. A. and Cantley, L. C. (2005) The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. J. Cell Biol. 170, 455-464 (Pubitemid 41126944)
160. Vazquez, F., Grossman, S. R., Takahashi, Y., Rokas, M. V., Nakamura, N. and Sellers, W. R. (2001) Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J. Biol. Chem. 276, 48627-48630
161. Lee, J. O., Yang, H., Georgescu, M. M., Di Cristofano, A., Maehama, T., Shi, Y., Dixon, J. E., Pandolfi, P. and Pavletich, N. P. (1999) Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99, 323-334 (Pubitemid 29519911)
162. Das, S., Dixon, J. E., Cho, W., Das, S., Dixon, J. E. and Cho, W. (2003) Membrane-binding and activation mechanism of PTEN. Proc. Natl. Acad. Sci. U.S.A. 100, 7491-7496 (Pubitemid 36759997)
163. Vazquez, F., Matsuoka, S., Sellers, W. R., Yanagida, T., Ueda, M. and Devreotes, P. N. (2006) Tumor suppressor PTEN acts through dynamic interaction with the plasma membrane. Proc. Natl. Acad. Sci. U.S.A. 103, 3633-3638 (Pubitemid 43376607)
164. Rahdar, M., Inoue, T., Meyer, T., Zhang, J., Vazquez, F. and Devreotes, P. N. (2009) A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. Proc. Natl. Acad. Sci. U.S.A. 106, 480-485
165. Rabinovsky, R., Pochanard, P., McNear, C., Brachmann, S. M., Duke-Cohan, J. S., Garraway, L. A. and Sellers, W. R. (2009) p85 associates with unphosphorylated PTEN and the PTEN-associated complex. Mol. Cell. Biol. 29, 5377-5388
166. He, J., de la Monte, S. and Wands, J. R. (2007) Acute ethanol exposure inhibits insulin signaling in the liver. Hepatology 46, 1791-1800
167. Taniguchi, C. M., Tran, T. T., Kondo, T., Luo, J., Ueki, K., Cantley, L. C. and Kahn, C. R. (2006) Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN. Proc. Natl. Acad. Sci. U.S.A. 103, 12093-12097 (Pubitemid 44215816)
168. Bonifant, C. L., Kim, J. S., Waldman, T., Bonifant, C. L., Kim, J.-S. and Waldman, T. (2007) NHERFs, NEP, MAGUKs, and more: interactions that regulate PTEN. J. Cell. Biochem. 102, 878-885 (Pubitemid 350036928)
169. +/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. U.S.A. 102, 10238-10243
170. Taniguchi, C. M., Winnay, J., Kondo, T., Bronson, R. T., Guimaraes, A. R., Aleman, J. O., Luo, J., Stephanopoulos, G., Weissleder, R., Cantley, L. C. et al. (2010) The phosphoinositide 3-kinase regulatory subunit p85α can exert tumor suppressor properties through negative regulation of growth factor signaling. Cancer Res. 70, 5305-5315
171. Joly, M., Kazlauskas, A., Fay, F. S. and Corvera, S. (1994) Disruption of PDGF receptor trafficking by mutation of its PI-3 kinase binding sites. Science 263, 684-687 (Pubitemid 24076296)
172. Rosenfeld, M. E., Bowen-Pope, D. F. and Ross, R. (1984) Platelet-derived growth factor: morphologic and biochemical studies of binding, internalization, and degradation. J. Cell. Physiol. 121, 263-274 (Pubitemid 14024040)
173. Joly, M., Kazlauskas, A. and Corvera, S. (1995) Phosphatidylinositol 3-kinase activity is required at a postendocytic step in platelet-derived growth factor receptor trafficking. J. Biol. Chem. 270, 13225-13230
174. Wu, H., Windmiller, D. A., Wang, L. and Backer, J. M. (2003) YXXM motifs in the PDGF-β receptor serve dual roles as phosphoinositide 3-kinase binding motifs and tyrosine-based endocytic sorting signals. J. Biol. Chem. 278, 40425-40428 (Pubitemid 37280851)
175. Sorkin, A. and von Zastrow, M. (2009) Endocytosis and signalling: intertwining molecular networks. Nat. Rev. Mol. Cell Biol. 10, 609-622
176. Barr, F. and Lambright, D. G. (2010) Rab GEFs and GAPs. Curr. Opin. Cell Biol. 22, 461-470
177. Bucci, C. and Chiariello, M. (2006) Signal transduction gRABs attention. Cell. Signalling 18, 1-8 (Pubitemid 41417767)
178. Nottingham, R. M. and Pfeffer, S. R. (2009) Defining the boundaries: Rab GEFs and GAPs. Proc. Natl. Acad. Sci. U.S.A. 106, 14185-14186
179. Brighouse, A., Dacks, J. and Field, M. (2010) Rab protein evolution and the history of the eukaryotic endomembrane system. Cell. Mol. Life Sci. 67, 3449-3465
180. Scheffzek, K., Ahmadian, M. R. and Wittinghofer, A. (1998) GTPase-activating proteins: helping hands to complement an active site. Trends Biochem. Sci. 23, 257-262 (Pubitemid 28343370)
181. Williams, R. L. and Urbe, S. (2007) The emerging shape of the ESCRT machinery. Nat. Rev. Mol. Cell Biol. 8, 355-368 (Pubitemid 46643239)
182. Raiborg, C. and Stenmark, H. (2009) The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445-452
183. Abella, J. V. and Park, M. (2009) Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am. J. Physiol. Endocrinol. Metab. 296, E973-E984
184. Sebastian, S., Settleman, J., Reshkin, S. J., Azzariti, A., Bellizzi, A. and Paradiso, A. (2006) The complexity of targeting EGFR signalling in cancer: from expression to turnover. Biochim. Biophys. Acta 1766, 120-139 (Pubitemid 44175636)
185. Mosesson, Y., Mills, G. B. and Yarden, Y. (2008) Derailed endocytosis: an emerging feature of cancer. Nat. Rev. Cancer 8, 835-850
186. Haglund, K., Rusten, T. E. and Stenmark, H. (2007) Aberrant receptor signaling and trafficking as mechanisms in oncogenesis. Crit. Rev. Oncog. 13, 39-74 (Pubitemid 47381249)
187. Simonsen, A., Lippe, R., Christoforidis, S., Gaullier, J. M., Brech, A., Callaghan, J., Toh, B. H., Murphy, C., Zerial, M. and Stenmark, H. (1998) EEA1 links PI3K function to Rab5 regulation of endosome fusion. Nature 394, 494-498 (Pubitemid 28373962)
188. Mills, I. G., Jones, A. T. and Clague, M. J. (1998) Involvement of the endosomal autoantigen EEA1 in homotypic fusion of early endosomes. Curr. Biol. 8, 881-884 (Pubitemid 28356049)
189. Christoforidis, S., McBride, H. M., Burgoyne, R. D. and Zerial, M. (1999) The Rab5 effector EEA1 is a core component of endosome docking. Nature 397, 621-625 (Pubitemid 29091948)
190. Simonsen, A., Gaullier, J. M., D'Arrigo, A. and Stenmark, H. (1999) The Rab5 effector EEA1 interacts directly with syntaxin-6. J. Biol. Chem. 274, 28857-28860
191. McBride, H. M., Rybin, V., Murphy, C., Giner, A., Teasdale, R. and Zerial, M. (1999) Oligomeric complexes link Rab5 effectors with NSF and drive membrane fusion via interactions between EEA1 and syntaxin 13. Cell 98, 377-386 (Pubitemid 29380572)
192. Christoforidis, S., Miaczynska, M., Ashman, K., Wilm, M., Zhao, L., Yip, S. C., Waterfield, M. D., Backer, J. M. and Zerial, M. (1999) Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nat. Cell Biol. 1, 249-252 (Pubitemid 129500945)
193. Gillooly, D. J., Morrow, I. C., Lindsay, M., Gould, R., Bryant, N. J., Gaullier, J.-M., Parton, R. G. and Stenmark, H. (2000) Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J. 19, 4577-4588
194. 2+-regulated pool of phosphatidylinositol-3- phosphate produced by phosphatidylinositol 3-kinase C2α on neurosecretory vesicles. Mol. Biol. Cell 19, 5593-5603
195. Krag, C., Malmberg, E. K. and Salcini, A. E. (2010) PI3KC2α, a class II PI3K, is required for dynamin-independent internalization pathways. J. Cell Sci. 123, 4240-4250
196. Gaidarov, I., Smith, M. E., Domin, J. and Keen, J. H. (2001) The class II phosphoinositide 3-kinase C2α is activated by clathrin and regulates clathrin-mediated membrane trafficking. Mol. Cell 7, 443-449 (Pubitemid 32206511)
197. Shin, H. W., Hayashi, M., Christoforidis, S., Lacas-Gervais, S., Hoepfner, S., Wenk, M. R., Modregger, J., Uttenweiler-Joseph, S., Wilm, M., Nystuen, A. et al. (2005) An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J. Cell Biol. 170, 607-618 (Pubitemid 41186935)
198. Subramani, D. and Alahari, S. K. (2010) Integrin-mediated function of Rab GTPases in cancer progression. Mol. Cancer 9, 312
199. Pellinen, T. and Ivaska, J. (2006) Integrin traffic. J. Cell Sci. 119, 3723-3731 (Pubitemid 44614425)
200. Lanzetti, L., Palamidessi, A., Areces, L., Scita, G. and Di Fiore, P. P. (2004) Rab5 is a signalling GTPase involved in actin remodelling by receptor tyrosine kinases. Nature 429, 309-314 (Pubitemid 38684817)
201. Spaargaren, M. and Bos, J. L. (1999) Rab5 induces Rac-independent lamellipodia formation and cell migration. Mol. Biol. Cell 10, 3239-3250 (Pubitemid 29489558)
202. Barbieri, M. A., Kong, C., Chen, P. I., Horazdovsky, B. F. and Stahl, P. D. (2003) The SRC homology 2 domain of Rin1 mediates its binding to the epidermal growth factor receptor and regulates receptor endocytosis. J. Biol. Chem. 278, 32027-32036 (Pubitemid 37048391)
203. Tall, G. G., Barbieri, M. A., Stahl, P. D. and Horazdovsky, B. F. (2001) Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1. Dev. Cell 1, 73-82 (Pubitemid 33586070)
204. Kong, C., Su, X., Chen, P.-I. and Stahl, P. D. (2007) Rin1 interacts with signal-transducing adaptor molecule (STAM) and mediates epidermal growth factor receptor trafficking and degradation. J. Biol. Chem. 282, 15294-15301 (Pubitemid 47093362)
205. Rubino, M., Miaczynska, M., Lippe, R. and Zerial, M. (2000) Selective membrane recruitment of EEA1 suggests a role in directional transport of clathrin-coated vesicles to early endosomes. J. Biol. Chem. 275, 3745-3748 (Pubitemid 30094593)
206. Lippe, R., Miaczynska, M., Rybin, V., Runge, A. and Zerial, M. (2001) Functional synergy between Rab5 effector Rabaptin-5 and exchange factor Rabex-5 when physically associated in a complex. Mol. Biol. Cell 12, 2219-2228 (Pubitemid 33049711)
207. Chamberlain, M. D., Chan, T., Oberg, J. C., Hawrysh, A. D., James, K. M., Saxena, A., Xiang, J. and Anderson, D. H. (2008) Disrupted RabGAP function of the p85 subunit of phosphatidylinositol 3-kinase results in cell transformation. J. Biol. Chem. 283, 15861-15868
208. Ciraolo, E., Iezzi, M., Marone, R., Marengo, S., Curcio, C., Costa, C., Azzolino, O., Gonella, C., Rubinetto, C., Wu, H. et al. (2008) Phosphoinositide 3-kinase p110βactivity: key role in metabolism and mammary gland cancer but not development. Sci. Signaling 1, ra3
209. Jia, S., Liu, Z., Zhang, S., Liu, P., Zhang, L., Lee, S. H., Zhang, J., Signoretti, S., Loda, M., Roberts, T. M. and Zhao, J. J. (2008) Essential roles of PI(3)K-p110β in cell growth, metabolism and tumorigenesis. Nature 454, 776-779
210. Barbieri, M. A., Fernandez-Pol, S., Hunker, C., Horazdovsky, B. H. and Stahl, P. D. (2004) Role of rab5 in EGF receptor-mediated signal transduction. Eur. J. Cell Biol. 83, 305-314 (Pubitemid 39307168)
211. Rink, J., Ghigo, E., Kalaidzidis, Y. and Zerial, M. (2005) Rab conversion as a mechanism of progression from early to late endosomes. Cell 122, 735-749 (Pubitemid 41242638)
212. Klippel, A., Escobedo, J. A., Hu, Q. and Williams, L. T. (1993) A region of the 85-kilodalton (kDa) subunit of phosphatidylinositol 3- kinase binds the 110-kDa catalytic subunit in vivo. Mol. Cell. Biol. 13, 5560-5566 (Pubitemid 23260658)
213. Cheung, L. W., Hennessy, B. T., Li, J., Yu, S., Myers, A. P., Djordjevic, B., Lu, Y., Stemke-Hale, K., Zhang, F., Ju, Z. et al. (2011) High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discovery 1, 170-185