T H E S I R H A N S K R E B S L E C T U R E How a lipid mediates tumour suppression Delivered on 29 June 2010 at the 35th FEBS Congress in Gothenburg, Sweden Harald Stenmark1,2 1 Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway 2 Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Montebello, Norway Keywords autophagy; cancer; cell division; cytokinesis; endocytosis; PI 3-kinase; tumour suppressor Correspondence H. Stenmark, Institute for Cancer Research, the Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway Fax: +47 22781845 Tel: +47 22781818 E-mail: stenmark@ulrik.uio.no Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/ onlineopen#OnlineOpen_Terms (Received 27 July 2010, revised 12 September 2010, accepted 4 October 2010) doi:10.1111/j.1742-4658.2010.07900.x Phosphorylated derivatives of the membrane lipid phosphatidylinositol (PtdIns), known as phosphoinositides (PIs), regulate membrane-proximal cellular processes by recruiting speciﬁc protein effectors involved in cell signalling, membrane trafﬁcking and cytoskeletal dynamics. Two PIs that are generated through the activities of distinct PI 3-kinases (PI3Ks) are of special interest in cancer research. PtdIns(3,4,5)P3, generated by class I PI3Ks, functions as tumour promotor by recruiting effectors involved in cell survival, proliferation, growth and motility. Conversely, there is evidence that PtdIns3P, generated by class III PI3K, functions in tumour suppression. Three subunits of the class III PI3K complex (Beclin 1, UVRAG and BIF-1) have been independently identiﬁed as tumour suppressors in mice and humans, and their mechanism of action in this context has been proposed to entail activation of autophagy, a catabolic pathway that is considered to mediate tumour suppression by scavenging damaged organ- elles that would otherwise cause DNA instability through the production of reactive oxygen species. Recent studies have revealed two additional functions of PtdIns3P that might contribute to its tumour suppressor activ- ity. The ﬁrst involves endosomal sorting and lysosomal downregulation of mitogenic receptors. The second involves regulation of cytokinesis, which is the ﬁnal stage of cell division. Further elucidation of the mechanisms of tumour suppression mediated by class III PI3K and PtdIns3P will identify novel Achilles’ heels of the cell’s defence against tumourigenesis and will be useful in the search for prognostic and diagnostic biomarkers in cancer. Introduction Eukaryotic cells contain very extensive intracellular membrane systems, and many vital cellular processes, such as metabolic reactions, signal transduction, cyto- skeletal rearrangements, protein sorting and regulation of membrane dynamics, occur partially or entirely at membrane–cytosol interfaces. The main advantages of executing biochemical reactions on membranes include the limitation of substrate diffusion (i.e. limited to two dimensions instead of three) and the possibility of con- ﬁning biochemical processes to restricted subcellular locations. The containment of cellular processes to intra- cellular membranes requires the reversible assembly of protein complexes onto speciﬁc membranes. A group Abbreviations EEA1, early endosomal autoantigen 1; ER, endoplasmic reticulum; ESCRT, endosomal sorting complex required for transport; ILV, intraluminal vesicles; PI, phosphoinositide; PI3K, phosphoinositide 3-kinase; PtdIns, phosphatidylinositol; PX, phox homology. FEBS Journal 277 (2010) 4837–4848 ª 2010 The Author Journal compilation ª 2010 FEBS 4837