H. Stenmark Acknowledgements I thank my mentors Sjur Olsnes and Marino Zerial, and my excellent co-workers at the Institute for Cancer Research. Research in my laboratory is generously sponsored by the Norwegian Cancer Society, the Research Council of Norway, the South-Eastern Norway Regional Health Authority, the European Research Foundation, and by an Advanced Grant from the European Research Council. References 1 Di Paolo G & De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657. 2 McCrea HJ & De Camilli P. (2009) Mutations in phos- phoinositide metabolizing enzymes and human disease. Physiology 24, 8–16. 3 Wong KK, Engelman JA & Cantley LC (2010) Target- ing the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20, 87–90. 4 Li L & Ross AH (2007) Why is PTEN an important tumor suppressor? J Cell Biochem 102, 1368–1374. 5 Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, Liang C, Jung JU, Cheng JQ, Mul JJ et al. (2007) Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 9, 1142–1151. 6 Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H & Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676. 7 Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH & Jung JU (2006) Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 8, 688–699. 8 Schu PV, Takegawa K, Fry MJ, Stack JH, Waterﬁeld MD & Emr SD (1993) Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260, 88–91. 9 Stack JH, DeWald DB, Takegawa K & Emr SD (1995) Vesicle-mediated protein transport: regulatory interac- tions between the Vps15 protein kinase and the Vps34 PtdIns 3-kinase essential for protein sorting to the vacu- ole in yeast. J Cell Biol 129, 321–334. 10 Kihara A, Noda T, Ishihara N & Ohsumi Y (2001) Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 152, 519–530. 11 Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Heintz N & Yue Z (2009) Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 11, 468–476. Krebs medal review: PtdIns3P in tumour suppression 12 Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T et al. (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11, 385–396. 13 Sun Q, Fan W, Chen K, Ding X, Chen S & Zhong Q (2008) Identiﬁcation of Barkor as a mammalian auto- phagy-speciﬁc factor for Beclin 1 and class III phospha- tidylinositol 3-kinase. Proc Natl Acad Sci USA 105, 19211–19216. 14 Itakura E, Kishi C, Inoue K & Mizushima N (2008) Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 19, 5360–5372. 15 Thoresen SB, Pedersen NM, Liestol K & Stenmark H (2010) A phosphatidylinositol 3-kinase class III sub- complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endo- cytic trafﬁc. Exp Cell Res, doi:10.1016/j.yexcr. 2010.07.008. 16 Gallop JL & McMahon HT (2005) BAR domains and membrane curvature: bringing your curves to the BAR. Biochem Soc Symp 72, 223–231. 17 Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman BT, Shokat KM & Williams RL (2010) Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327, 1638–1642. 18 Furuya T, Kim M, Lipinski M, Li J, Kim D, Lu T, Shen Y, Rameh L, Yankner B, Tsai L-H et al. (2010) Negative regulation of Vps34 by Cdk mediated phos- phorylation. Mol Cell 38, 500–511. 19 Stenmark H, Aasland R, Toh BH & D’Arrigo A (1996) Endosomal localization of the autoantigen EEA1 is mediated by a zinc-binding FYVE ﬁnger. J Biol Chem 271, 24048–24054. 20 Patki V, Virbasius J, Lane WS, Toh BH, Shpetner HS & Corvera S (1997) Identiﬁcation of an early endosomal protein regulated by phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 94, 7326–7330. 21 Gaullier J-M, Simonsen A, D’Arrigo A, Bremnes B, Aasland R & Stenmark H (1998) FYVE ﬁngers bind PtdIns(3)P. Nature 394, 432–433. 22 Burd CG & Emr SD (1998) Phosphatidylinositol(3)- phosphate signaling mediated by speciﬁc binding to RING FYVE domains. Mol Cell 2, 157–162. 23 Patki V, Lawe DC, Corvera S, Virbasius JV & Chawla A (1998) A functional PtdIns(3)P-binding motif. Nature 394, 433–434. 24 Ellson CD, Gobert-Gosse S, Anderson KE, Davidson K, Erdjument-Bromage H, Tempst P, Thuring JW, Cooper MA, Lim Z-Y, Holmes AB et al. (2001) Phos- phatidylinositol 3-phosphate regulates the neutrophil oxidase complex by binding to the PX domain of p40phox. Nature Cell Biol 3, 679–682. FEBS Journal 277 (2010) 4837–4848 ª 2010 The Author Journal compilation ª 2010 FEBS 4845