- Kok, K., Geering, B. & Vanhaesebroeck, B. Regulation of phosphoinositide 3-kinase expression in health and disease. Trends Biochem. Sci. 34, 115–127 (2009).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed Google Scholar
- Vanhaesebroeck, B., Ali, K., Bilancio, A., Geering, B. & Foukas, L. C. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem. Sci. 30, 194–204 (2005).
Article CAS PubMed Google Scholar
- Chamberlain, M. D. et al. Disrupted RabGAP function of the p85 subunit of phosphatidylinositol 3-kinase results in cell transformation. J. Biol. Chem. 283, 15861–15868 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Vanhaesebroeck, B. et al. P110δ, a novel phosphoinositide 3-kinase in leukocytes. Proc. Natl Acad. Sci. USA 94, 4330–4335 (1997).
Article CAS PubMed PubMed Central Google Scholar
- Inukai, K. et al. Five isoforms of the phosphatidylinositol 3-kinase regulatory subunit exhibit different associations with receptor tyrosine kinases and their tyrosine phosphorylations. FEBS Lett. 490, 32–38 (2001).
Article CAS PubMed Google Scholar
- Xia, X. & Serrero, G. Multiple forms of p55PIK, a regulatory subunit of phosphoinositide 3-kinase, are generated by alternative initiation of translation. Biochem. J. 341, 831–837 (1999).
Article CAS PubMed PubMed Central Google Scholar
- Foukas, L. C. et al. Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366–370 (2006). Using mice expressing a kinase-dead version of the endogenous PI3K p110α, this paper documents an isoform-selective role of p110α in insulin signalling, with no involvement of p110β. The underlying mechanism is a selective recruitment and activation of p110α over p110β to insulin receptor complexes, despite p110β often being expressed at higher levels in insulin-responsive tissues.
Article CAS PubMed Google Scholar
- Janas, M. L. et al. The effect of deleting p110δ on the phenotype and function of PTEN-deficient B cells. J. Immunol. 180, 739–746 (2008).
Article CAS PubMed Google Scholar
- Papakonstanti, E. A. et al. Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages. J. Cell Sci. 121, 4124–4133 (2008).
Article CAS PubMed Google Scholar
- Garcia, Z., Kumar, A., Marques, M., Cortes, I. & Carrera, A. C. Phosphoinositide 3-kinase controls early and late events in mammalian cell division. EMBO J. 25, 655–661 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Kurig, B. et al. Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110γ. Proc. Natl Acad. Sci. USA 106, 20312–20317 (2009).
Article PubMed PubMed Central Google Scholar
- Bohnacker, T. et al. PI3Kγ adaptor subunits define coupling to degranulation and cell motility by distinct PtdIns(3,4,5)P3 pools in mast cells. Sci. Signal 2, ra27 (2009). This is the first reference to document non-redundancy between the regulatory subunits of p110γ, showing that the regulatory subunits can diversify the p110γ signal.
Article CAS PubMed Google Scholar
- Gupta, S. et al. Binding of ras to phosphoinositide 3-kinase p110α is required for ras-driven tumorigenesis in mice. Cell 129, 957–968 (2007).
Article CAS PubMed Google Scholar
- Suire, S. et al. Gβγs and the Ras binding domain of p110γ are both important regulators of PI(3)Kγ signalling in neutrophils. Nature Cell Biol. 8, 1303–1309 (2006).
Article CAS PubMed Google Scholar
- Rodriguez-Viciana, P., Sabatier, C. & McCormick, F. Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol. Cell. Biol. 24, 4943–4954 (2004).
Article CAS PubMed PubMed Central Google Scholar
- Delgado, P. et al. Essential function for the GTPase TC21 in homeostatic antigen receptor signaling. Nature Immunol. 10, 880–888 (2009).
Article CAS Google Scholar
- Marques, M. et al. Phosphoinositide 3-kinases p110α and p110β regulate cell cycle entry, exhibiting distinct activation kinetics in G1 phase. Mol. Cell. Biol. 28, 2803–2814 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Kang, S., Denley, A., Vanhaesebroeck, B. & Vogt, P. K. Oncogenic transformation induced by the p110β, -γ, and -δ isoforms of class I phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 103, 1289–1294 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Vanhaesebroeck, B. et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 70, 535–602 (2001).
Article CAS PubMed Google Scholar
- Jimenez, C., Hernandez, C., Pimentel, B. & Carrera, A. C. The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras. J. Biol. Chem. 277, 41556–41562 (2002).
Article CAS PubMed Google Scholar
- Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase γ. Cell 103, 931–943 (2000).
Article CAS PubMed Google Scholar
- Orme, M. H., Alrubaie, S., Bradley, G. L., Walker, C. D. & Leevers, S. J. Input from Ras is required for maximal PI(3)K signalling in Drosophila. Nature Cell Biol. 8, 1298–1302 (2006). Together with references 14 and 15, this paper shows that Ras is important in PI3K signalling in a physiological context.
Article CAS PubMed Google Scholar
- Kurosu, H. et al. Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110β is synergistically activated by the βγ subunits of G proteins and phosphotyrosyl peptide. J. Biol. Chem. 272, 24252–24256 (1997).
Article CAS PubMed Google Scholar
- Christoforidis, S. et al. Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nature Cell Biol. 1, 249–252 (1999).
Article CAS PubMed Google Scholar
- Shin, H. W. et al. An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J. Cell Biol. 170, 607–618 (2005).
Article CAS PubMed PubMed Central Google Scholar
- Kurosu, H. & Katada, T. Association of phosphatidylinositol 3-kinase composed of p110β-catalytic and p85-regulatory subunits with the small GTPase Rab5. J. Biochem. 130, 73–78 (2001).
Article CAS PubMed Google Scholar
- Ciraolo, E. et al. Phosphoinositide 3-kinase p110β activity: key role in metabolism and mammary gland cancer but not development. Sci. Signal 1, ra3 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Jia, S. et al. Essential roles of PI(3)K-p110β in cell growth, metabolism and tumorigenesis. Nature 454, 776–779 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Eisenberg, S. & Henis, Y. I. Interactions of Ras proteins with the plasma membrane and their roles in signaling. Cell Signal. 20, 31–39 (2008).
Article CAS PubMed Google Scholar
- Plowman, S. J. & Hancock, J. F. Ras signaling from plasma membrane and endomembrane microdomains. Biochim. Biophys. Acta 1746, 274–283 (2005).
Article CAS PubMed Google Scholar
- Maier, U., Babich, A. & Nurnberg, B. 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 (1999).
Article CAS PubMed Google Scholar
- Stoyanov, B. et al. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science 269, 690–693 (1995).
Article CAS PubMed Google Scholar
- Stephens, L. et al. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein β γ subunits. Cell 77, 83–93 (1994).
Article CAS PubMed Google Scholar
- Guillermet-Guibert, J. et al. The p110β isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110γ. Proc. Natl Acad. Sci. USA 105, 8292–8297 (2008). Using genetic and pharmacological tools, this study clearly establishes a role for p110β in GPCR signalling, which was previously inferred by indirect means in references 24 and 32.
Article PubMed PubMed Central Google Scholar
- Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation. Science 287, 1049–1053 (2000).
Article CAS PubMed Google Scholar
- Ballou, L. M., Chattopadhyay, M., Li, Y., Scarlata, S. & Lin, R. Z. Gαq binds to p110α/p85α phosphoinositide 3-kinase and displaces Ras. Biochem. J. 394, 557–562 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Taboubi, S. et al. Gα q/11-coupled P2Y2 nucleotide receptor inhibits human keratinocyte spreading and migration. FASEB J. 21, 4047–4058 (2007).
Article CAS PubMed Google Scholar
- Durand, C. A. et al. Phosphoinositide 3-kinase p110δ regulates natural antibody production, marginal zone and B-1 B cell function, and autoantibody responses. J. Immunol. 183, 5673–5684 (2009).
Article CAS PubMed Google Scholar
- Reif, K. et al. Cutting edge: differential roles for phosphoinositide 3-kinases, p110γ and p110δ, in lymphocyte chemotaxis and homing. J. Immunol. 173, 2236–2240 (2004).
Article CAS PubMed Google Scholar
- Saudemont, A. et al. p110γ and p110δ isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. Proc. Natl Acad. Sci. USA 106, 5795–5800 (2009).
Article PubMed PubMed Central Google Scholar
- Bousquet, C. et al. Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway. EMBO J. 25, 3943–3954 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Tang, X. & Downes, C. P. Purification and characterization of Gβγ-responsive phosphoinositide 3-kinases from pig platelet cytosol. J. Biol. Chem. 272, 14193–14199 (1997).
Article CAS PubMed Google Scholar
- Kubo, H., Hazeki, K., Takasuga, S. & Hazeki, O. Specific role for p85/p110β in GTP-binding-protein-mediated activation of Akt. Biochem. J. 392, 607–614 (2005).
Article CAS PubMed PubMed Central Google Scholar
- Dumont, J. E., Dremier, S., Pirson, I. & Maenhaut, C. Cross signaling, cell specificity, and physiology. Am. J. Physiol. Cell Physiol. 283, C2–C28 (2002).
Article CAS PubMed Google Scholar
- Bilancio, A. et al. Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells. Blood 107, 642–650 (2006).
Article CAS PubMed Google Scholar
- Lemmon, M. A. Membrane recognition by phospholipid-binding domains. Nature Rev. Mol. Cell Biol. 9, 99–111 (2008).
Article CAS Google Scholar
- Sato, M., Ueda, Y., Takagi, T. & Umezawa, Y. Production of PtdInsP3 at endomembranes is triggered by receptor endocytosis. Nature Cell Biol. 5, 1016–1022 (2003).
Article PubMed Google Scholar
- Lindsay, Y. et al. Localization of agonist-sensitive PtdIns(3,4,5)P3 reveals a nuclear pool that is insensitive to PTEN expression. J. Cell Sci. 119, 5160–5168 (2006).
Article CAS PubMed Google Scholar
- Marques, M. et al. Specific function of phosphoinositide 3-kinase β in the control of DNA replication. Proc. Natl Acad. Sci. USA 106, 7525–7530 (2009).
Article PubMed PubMed Central Google Scholar
- Backer, J. M. Substrate specificity: PI(3)Kγ has it both ways. Nature Cell Biol. 7, 773–774 (2005).
Article CAS PubMed Google Scholar
- Vanhaesebroeck, B. et al. Autophosphorylation of p110δ phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo. EMBO J. 18, 1292–1302 (1999).
Article CAS PubMed PubMed Central Google Scholar
- Czupalla, C. et al. Identification and characterization of the autophosphorylation sites of phosphoinositide 3-kinase isoforms β and γ. J. Biol. Chem. 278, 11536–11545 (2003).
Article CAS PubMed Google Scholar
- Hirsch, E., Braccini, L., Ciraolo, E., Morello, F. & Perino, A. Twice upon a time: PI3K's secret double life exposed. Trends Biochem. Sci. 34, 244–248 (2009).
Article CAS PubMed Google Scholar
- Patrucco, E. et al. PI3Kγ modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118, 375–387 (2004). The first paper to show that a gene deletion of a PI3K can give a different phenotype to that of a kinase-dead PI3K, whereby the gene is mutated and not deleted.
Article CAS PubMed Google Scholar
- Lehmann, K. et al. PI3Kγ controls oxidative burst in neutrophils via interaction with PKCα and p47phox. Biochem. J. 419, 603–610 (2008).
Article CAS Google Scholar
- 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). Used pharmacological tools to reach the same conclusion as reference 8. Together with reference 8, this paper also shows that relative expression levels do not necessarily correlate with the relative importance of PI3Ks.
Article CAS PubMed PubMed Central Google Scholar
- Vasudevan, K. M. et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16, 21–32 (2009). This paper shows that Akt, the classical downstream target of PI3K, is not necessarily switched on in cells with oncogenically mutated p110α.
Article CAS PubMed PubMed Central Google Scholar
- Papakonstanti, E. A., Ridley, A. J. & Vanhaesebroeck, B. The p110δ isoform of PI 3-kinase negatively controls RhoA and PTEN. EMBO J. 26, 3050–3061 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Eickholt, B. J. et al. Control of axonal growth and regeneration of sensory neurons by the p110δ PI 3-kinase. PLoS ONE 2, e869 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Graupera, M. et al. Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration. Nature 453, 662–666 (2008).
Article CAS PubMed Google Scholar
- Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004). The first paper to document high frequency mutations in PIK3CA , which encodes p110α, in cancer
Article CAS PubMed Google Scholar
- Cornillet-Lefebvre, P. et al. Constitutive phosphoinositide 3-kinase activation in acute myeloid leukemia is not due to p110δ mutations. Leukemia 20, 374–376 (2006).
Article CAS PubMed Google Scholar
- Thomas, R. K. et al. High-throughput oncogene mutation profiling in human cancer. Nature Genet. 39, 347–351 (2007).
Article CAS PubMed Google Scholar
- Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).
Article CAS PubMed Google Scholar
- Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).
- Vogt, P. K., Kang, S., Elsliger, M. A. & Gymnopoulos, M. Cancer-specific mutations in phosphatidylinositol 3-kinase. Trends Biochem. Sci. 32, 342–349 (2007).
Article CAS PubMed Google Scholar
- Zhao, L. & Vogt, P. K. Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl Acad. Sci. USA 105, 2652–2657 (2008).
Article PubMed PubMed Central Google Scholar
- Amzel, L. M. et al. Structural comparisons of class I phosphoinositide 3-kinases. Nature Rev. Cancer 8, 665–669 (2008).
Article CAS Google Scholar
- Zhao, J. J. et al. The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc. Natl Acad. Sci. USA 102, 18443–18448 (2005).
Article CAS PubMed PubMed Central Google Scholar
- Shayesteh, L. et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nature Genet. 21, 99–102 (1999).
Article CAS PubMed Google Scholar
- Ikenoue, T. et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res. 65, 4562–4567 (2005).
Article CAS PubMed Google Scholar
- Kang, S., Bader, A. G., Zhao, L. & Vogt, P. K. Mutated PI 3-kinases: cancer targets on a silver platter. Cell Cycle 4, 578–581 (2005).
Article CAS PubMed Google Scholar
- Zhao, L. & Vogt, P. K. Class I PI3K in oncogenic cellular transformation. Oncogene 27, 5486–5496 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Gymnopoulos, M., Elsliger, M. A. & Vogt, P. K. Rare cancer-specific mutations in PIK3CA show gain of function. Proc. Natl Acad. Sci. USA 104, 5569–5574 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Mandelker, D. et al. A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane. Proc. Natl Acad. Sci. USA 106, 16996–17001 (2009).
Article PubMed PubMed Central Google Scholar
- Miled, N. et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317, 239–242 (2007).
Article CAS PubMed Google Scholar
- Carson, J. D. et al. Effects of oncogenic p110α subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. Biochem. J. 409, 519–524 (2008).
Article CAS PubMed Google Scholar
- Chaussade, C., Cho, K., Mawson, C., Rewcastle, G. W. & Shepherd, P. R. Functional differences between two classes of oncogenic mutation in the PIK3CA gene. Biochem. Biophys. Res. Commun. 381, 577–581 (2009).
Article CAS PubMed Google Scholar
- Beeton, C. A., Chance, E. M., Foukas, L. C. & Shepherd, P. R. Comparison of the kinetic properties of the lipid- and protein-kinase activities of the p110α and p110β catalytic subunits of class-Ia phosphoinositide 3-kinases. Biochem. J. 350, 353–359 (2000).
Article CAS PubMed PubMed Central Google Scholar
- Meier, T. I. et al. Cloning, expression, purification, and characterization of the human class Ia phosphoinositide 3-kinase isoforms. Protein Expr. Purif. 35, 218–224 (2004).
Article CAS PubMed Google Scholar
- Pang, H. et al. Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA phosphoinositide 3-kinase. Cancer Res. 69, 8868–8876 (2009). This manuscript shows that different mutations in PIK3CA can have discrete biological outputs in mammalian cells.
Article CAS PubMed PubMed Central Google Scholar
- Morrow, C. J., Gray, A. & Dive, C. Comparison of phosphatidylinositol-3-kinase signalling within a panel of human colorectal cancer cell lines with mutant or wild-type PIK3CA. FEBS Lett. 579, 5123–5128 (2005). This was the first study to show that there is no good correlation between the presence of PIK3CA mutations and the steady state or growth factor-stimulated activity of PI3K and Akt.
Article CAS PubMed Google Scholar
- Stemke-Hale, K. et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 68, 6084–6091 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Jaiswal, B. S. et al. Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell 16, 463–474 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Martin-Berenjeno, I. & Vanhaesebroeck, B. PI3K regulatory subunits lose control in cancer. Cancer Cell 16, 449–450 (2009).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- 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).
Article CAS PubMed Google Scholar
- Prior, I. A. & Clague, M. J. Localization of a class II phosphatidylinositol 3-kinase, PI3KC2α, to clathrin-coated vesicles. Mol. Cell Biol. Res. Commun. 1, 162–166 (1999).
Article CAS PubMed Google Scholar
- Domin, J., Gaidarov, I., Smith, M. E., Keen, J. H. & Waterfield, M. D. The class II phosphoinositide 3-kinase PI3K-C2α is concentrated in the trans-Golgi network and present in clathrin-coated vesicles. J. Biol. Chem. 275, 11943–11950 (2000).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed Google Scholar
- Banfic, H. et al. Epidermal growth factor stimulates translocation of the class II phosphoinositide 3-kinase PI3K-C2β to the nucleus. Biochem. J. 422, 53–60 (2009).
Article CAS PubMed Google Scholar
- Didichenko, S. A. & Thelen, M. Phosphatidylinositol 3-kinase c2α contains a nuclear localization sequence and associates with nuclear speckles. J. Biol. Chem. 276, 48135–48142 (2001).
Article CAS PubMed Google Scholar
- Song, X. et al. Phox homology domains specifically bind phosphatidylinositol phosphates. Biochemistry 40, 8940–8944 (2001).
Article CAS PubMed Google Scholar
- Stahelin, R. V. et al. Structural and membrane binding analysis of the Phox homology domain of phosphoinositide 3-kinase-C2α. J. Biol. Chem. 281, 39396–39406 (2006).
Article CAS PubMed Google Scholar
- Falasca, M. & Maffucci, T. Role of class II phosphoinositide 3-kinase in cell signalling. Biochem. Soc. Trans. 35, 211–214 (2007).
Article CAS PubMed Google Scholar
- Falasca, M. & Maffucci, T. Emerging roles of phosphatidylinositol 3-monophosphate as a dynamic lipid second messenger. Arch. Physiol. Biochem. 112, 274–284 (2006).
Article CAS PubMed Google Scholar
- Falasca, M. & Maffucci, T. Rethinking phosphatidylinositol 3-monophosphate. Biochim. Biophys. Acta 1793, 1795–1803 (2009).
Article CAS PubMed Google Scholar
- Arcaro, A. et al. Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol. Cell. Biol. 20, 3817–3830 (2000).
Article CAS PubMed PubMed Central Google Scholar
- Wheeler, M. & Domin, J. Recruitment of the class II phosphoinositide 3-kinase C2β to the epidermal growth factor receptor: role of Grb2. Mol. Cell. Biol. 21, 6660–6667 (2001).
Article CAS PubMed PubMed Central Google Scholar
- Katso, R. M. et al. Phosphoinositide 3-kinase C2β regulates cytoskeletal organization and cell migration via Rac-dependent mechanisms. Mol. Biol. Cell 17, 3729–3744 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Das, M. et al. Regulation of neuron survival through an intersectin-phosphoinositide 3′-kinase C2β-AKT pathway. Mol. Cell. Biol. 27, 7906–7917 (2007).
Article CAS PubMed PubMed Central Google Scholar
- Gaidarov, I., Zhao, Y. & Keen, J. H. Individual phosphoinositide 3-kinase C2α domain activities independently regulate clathrin function. J. Biol. Chem. 280, 40766–40772 (2005).
Article CAS PubMed Google Scholar
- Gaidarov, I., Smith, M. E., Domin, J. & Keen, J. H. The class II phosphoinositide 3-kinase C2α is activated by clathrin and regulates clathrin-mediated membrane trafficking. Mol. Cell 7, 443–449 (2001).
Article CAS PubMed Google Scholar
- Wheeler, M. & Domin, J. The N-terminus of phosphoinositide 3-kinase-C2β regulates lipid kinase activity and binding to clathrin. J. Cell Physiol. 206, 586–593 (2006).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- Falasca, M. et al. The role of phosphoinositide 3-kinase C2α in insulin signaling. J. Biol. Chem. 282, 28226–28236 (2007).
Article CAS PubMed Google Scholar
- Wen, P. J. et al. Ca2+-regulated pool of phosphatidylinositol-3-phosphate produced by phosphatidylinositol 3-kinase C2α on neurosecretory vesicles. Mol. Biol. Cell 19, 5593–5603 (2008). References 107–109 show that class II PI3Ks can produce PtdIns3P in an agonist-dependent manner in mammalian cells.
Article CAS PubMed PubMed Central Google Scholar
- Domin, J. et al. The class II phosphoinositide 3-kinase PI3K-C2β regulates cell migration by a PtdIns3P dependent mechanism. J. Cell Physiol. 205, 452–462 (2005).
Article CAS PubMed Google Scholar
- Maffucci, T. et al. Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration. J. Cell Biol. 169, 789–799 (2005).
Article CAS PubMed PubMed Central Google Scholar
- Sindic, A., Aleksandrova, A., Fields, A. P., Volinia, S. & Banfic, H. Presence and activation of nuclear phosphoinositide 3-kinase C2β during compensatory liver growth. J. Biol. Chem. 276, 17754–17761 (2001).
Article CAS PubMed Google Scholar
- Gillooly, D. J. et al. Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J. 19, 4577–4588 (2000).
Article CAS PubMed PubMed Central Google Scholar
- Gillooly, D. J., Raiborg, C. & Stenmark, H. Phosphatidylinositol 3-phosphate is found in microdomains of early endosomes. Histochem. Cell Biol. 120, 445–453 (2003).
Article CAS PubMed Google Scholar
- Wurmser, A. E. & Emr, S. D. Phosphoinositide signaling and turnover: PtdIns(3)P, a regulator of membrane traffic, is transported to the vacuole and degraded by a process that requires lumenal vacuolar hydrolase activities. EMBO J. 17, 4930–4942 (1998).
Article CAS PubMed PubMed Central Google Scholar
- Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006).
Article CAS PubMed Google Scholar
- Hurley, J. H. Membrane binding domains. Biochim. Biophys. Acta 1761, 805–811 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Birkeland, H. C. & Stenmark, H. Protein targeting to endosomes and phagosomes via FYVE and PX domains. Curr. Top. Microbiol Immunol. 282, 89–115 (2004).
CAS PubMed Google Scholar
- Meunier, F. A. et al. Phosphatidylinositol 3-kinase C2α is essential for ATP-dependent priming of neurosecretory granule exocytosis. Mol. Biol. Cell 16, 4841–4851 (2005).
Article CAS PubMed PubMed Central Google Scholar
- Harada, K., Truong, A. B., Cai, T. & Khavari, P. A. The class II phosphoinositide 3-kinase C2β is not essential for epidermal differentiation. Mol. Cell. Biol. 25, 11122–11130 (2005).
Article CAS PubMed PubMed Central Google Scholar
- Ashrafi, K. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268–272 (2003).
Article CAS PubMed Google Scholar
- MacDougall, L. K., Gagou, M. E., Leevers, S. J., Hafen, E. & Waterfield, M. D. Targeted expression of the class II phosphoinositide 3-kinase in Drosophila melanogaster reveals lipid kinase-dependent effects on patterning and interactions with receptor signaling pathways. Mol. Cell. Biol. 24, 796–808 (2004).
Article CAS PubMed PubMed Central Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- Simonsen, A. & Tooze, S. A. Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J. Cell Biol. 186, 773–782 (2009).
Article CAS PubMed PubMed Central Google Scholar
- Liang, C. et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nature Cell Biol. 8, 688–699 (2006).
Article CAS PubMed Google Scholar
- Takahashi, Y. et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nature Cell Biol. 9, 1142–1151 (2007).
Article CAS PubMed Google Scholar
- Schu, P. V. et al. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260, 88–91 (1993). Together with reference 124, this paper reveals for the first time the role of Vps34 in endosomal protein sorting.
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- Xue, Y. et al. Genetic analysis of the myotubularin family of phosphatases in Caenorhabditis elegans. J. Biol. Chem. 278, 34380–34386 (2003).
Article CAS PubMed Google Scholar
- Roggo, L. et al. Membrane transport in Caenorhabditis elegans: an essential role for VPS34 at the nuclear membrane. EMBO J. 21, 1673–1683 (2002).
Article CAS PubMed PubMed Central Google Scholar
- Nobukuni, T. et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc. Natl Acad. Sci. USA 102, 14238–14243 (2005).
Article CAS PubMed PubMed Central Google Scholar
- Byfield, M. P., Murray, J. T. & Backer, J. M. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J. Biol. Chem. 280, 33076–33082 (2005).
Article CAS PubMed Google Scholar
- Slessareva, J. E., Routt, S. M., Temple, B., Bankaitis, V. A. & Dohlman, H. G. Activation of the phosphatidylinositol 3-kinase Vps34 by a G protein α subunit at the endosome. Cell 126, 191–203 (2006).
Article CAS PubMed Google Scholar
- Windmiller, D. A. & Backer, J. M. Distinct phosphoinositide 3-kinases mediate mast cell degranulation in response to G-protein-coupled versus FcɛRI receptors. J. Biol. Chem. 278, 11874–11878 (2003). Together with reference 134, this paper demonstrates that Vps34 can be activated by GPCRs.
Article CAS PubMed Google Scholar
- Backer, J. M. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem. J. 410, 1–17 (2008).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- Juhasz, G. et al. The class III PI(3)K Vps34 promotes autophagy and endocytosis but not TOR signaling in Drosophila. J. Cell Biol. 181, 655–666 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008).
Article PubMed PubMed Central Google Scholar
- Futter, C. E., Collinson, L. M., Backer, J. M. & Hopkins, C. R. Human VPS34 is required for internal vesicle formation within multivesicular endosomes. J. Cell Biol. 155, 1251–1264 (2001).
Article CAS PubMed PubMed Central Google Scholar
- Murray, J. T., Panaretou, C., Stenmark, H., Miaczynska, M. & Backer, J. M. Role of Rab5 in the recruitment of hVps34/p150 to the early endosome. Traffic 3, 416–427 (2002).
Article CAS PubMed Google Scholar
- Cao, C., Backer, J. M., Laporte, J., Bedrick, E. J. & Wandinger-Ness, A. Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking. Mol. Biol. Cell 19, 3334–3346 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Cao, C., Laporte, J., Backer, J. M., Wandinger-Ness, A. & Stein, M. P. Myotubularin lipid phosphatase binds the hVPS15/hVPS34 lipid kinase complex on endosomes. Traffic 8, 1052–1067 (2007).
Article CAS PubMed Google Scholar
- Siddhanta, U., McIlroy, J., Shah, A., Zhang, Y. & Backer, J. M. Distinct roles for the p110α and hVPS34 phosphatidylinositol 3′-kinases in vesicular trafficking, regulation of the actin cytoskeleton, and mitogenesis. J. Cell Biol. 143, 1647–1659 (1998).
Article CAS PubMed PubMed Central Google Scholar
- Stein, M. P., Feng, Y., Cooper, K. L., Welford, A. M. & Wandinger-Ness, A. Human VPS34 and p150 are Rab7 interacting partners. Traffic 4, 754–771 (2003).
Article CAS PubMed Google Scholar
- Vieira, O. V. et al. Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. J. Cell Biol. 155, 19–25 (2001).
Article CAS PubMed PubMed Central Google Scholar
- Ellson, C. D. et al. Phosphatidylinositol 3-phosphate is generated in phagosomal membranes. Curr. Biol. 11, 1631–1635 (2001). Together with reference 146, this paper is the first to show PtdIns3P production in phagocytosis, mainly produced by Vps34.
Article CAS PubMed Google Scholar
- Anderson, K. E. et al. CD18-dependent activation of the neutrophil NADPH oxidase during phagocytosis of E. coli or, S. aureus is regulated by class III but not class I or II PI3Ks. Blood 112, 5202–5211 (2008).
Article CAS PubMed Google Scholar
- Chua, J. & Deretic, V. Mycobacterium tuberculosis reprograms waves of phosphatidylinositol 3-phosphate on phagosomal organelles. J. Biol. Chem. 279, 36982–36992 (2004).
Article CAS PubMed Google Scholar
- Fratti, R. A., Backer, J. M., Gruenberg, J., Corvera, S. & Deretic, V. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J. Cell Biol. 154, 631–644 (2001).
Article CAS PubMed PubMed Central Google Scholar
- Kinchen, J. M. et al. A pathway for phagosome maturation during engulfment of apoptotic cells. Nature Cell Biol. 10, 556–566 (2008).
Article CAS PubMed Google Scholar
- Ellson, C., Davidson, K., Anderson, K., Stephens, L. R. & Hawkins, P. T. PtdIns3P binding to the PX domain of p40phox is a physiological signal in NADPH oxidase activation. EMBO J. 25, 4468–4478 (2006).
Article CAS PubMed PubMed Central Google Scholar
- Wu, J., Randle, K. E. & Wu, L. P. ird1 is a Vps15 homologue important for antibacterial immune responses in Drosophila. Cell. Microbiol 9, 1073–1085 (2007).
Article CAS PubMed Google Scholar
- Downes, C. P., Gray, A. & Lucocq, J. M. Probing phosphoinositide functions in signaling and membrane trafficking. Trends Cell Biol. 15, 259–268 (2005).
Article CAS PubMed Google Scholar
- Rusten, T. E. & Stenmark, H. Analyzing phosphoinositides and their interacting proteins. Nature Methods 3, 251–258 (2006).
Article CAS PubMed Google Scholar
- Gold, M. R., Duronio, V., Saxena, S. P., Schrader, J. W. & Aebersold, R. Multiple cytokines activate phosphatidylinositol 3-kinase in hemopoietic cells. Association of the enzyme with various tyrosine-phosphorylated proteins. J. Biol. Chem. 269, 5403–5412 (1994).
CAS PubMed Google Scholar
- Nicot, A. S. & Laporte, J. Endosomal phosphoinositides and human diseases. Traffic 9, 1240–1249 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).
Article CAS PubMed PubMed Central Google Scholar
- Kroemer, G. & Levine, B. Autophagic cell death: the story of a misnomer. Nature Rev. Mol. Cell Biol. 9, 1004–1010 (2008).
Article CAS Google Scholar
- Johnson, E. E., Overmeyer, J. H., Gunning, W. T. & Maltese, W. A. Gene silencing reveals a specific function of hVps34 phosphatidylinositol 3-kinase in late versus early endosomes. J. Cell Sci. 119, 1219–1232 (2006).
Article CAS PubMed Google Scholar
- Carter, C. J. Multiple genes and factors associated with bipolar disorder converge on growth factor and stress activated kinase pathways controlling translation initiation: implications for oligodendrocyte viability. Neurochem. Int. 50, 461–490 (2007).
Article CAS PubMed Google Scholar
- Tang, R. et al. Investigation of variants in the promoter region of PIK3C3 in schizophrenia. Neurosci. Lett. 437, 42–44 (2008).
Article CAS PubMed Google Scholar
- Kang, S. et al. Suppression of the α-isoform of class II phosphoinositide 3-kinase gene expression leads to apoptotic cell death. Biochem. Biophys. Res. Commun. 329, 6–10 (2005).
Article CAS PubMed Google Scholar
- Elis, W. et al. Down-regulation of class II phosphoinositide 3-kinase α expression below a critical threshold induces apoptotic cell death. Mol. Cancer Res. 6, 614–623 (2008).
Article CAS PubMed Google Scholar
- Dove, S. K. et al. Svp1p defines a family of phosphatidylinositol 3, 5-bisphosphate effectors. EMBO J. 23, 1922–1933 (2004).
Article CAS PubMed PubMed Central Google Scholar
- Dove, S. K., Dong, K., Kobayashi, T., Williams, F. K. & Michell, R. H. Phosphatidylinositol 3, 5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function. Biochem. J. 419, 1–13 (2009).
Article CAS PubMed Google Scholar
- Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed Google Scholar
- Ooms, L. M. et al. The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem. J. 419, 29–49 (2009).
Article CAS PubMed Google Scholar
- 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).
Article CAS PubMed PubMed Central Google Scholar
- Heenan, E. J. et al. Structure and function of Vps15 in the endosomal G protein signaling pathway. Biochemistry 48, 6390–6401 (2009).
Article CAS PubMed Google Scholar
- Fimia, G. M. et al. Ambra1 regulates autophagy and development of the nervous system. Nature 447, 1121–1125 (2007).
CAS PubMed Google Scholar
- Matsunaga, K. et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nature Cell Biol. 11, 385–396 (2009).
Article CAS PubMed Google Scholar
- Zhong, Y. et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nature Cell Biol. 11, 468–476 (2009).
Article CAS PubMed Google Scholar