H. Stenmark Krebs medal review: PtdIns3P in tumour suppression (FYVE protein on centrosomes) as a PtdIns3P effector in cytokinesis. FYVE-CENT localizes to the centro- some in interphase cells and translocates to the mid- body during telophase. This translocation appears to be mediated by the microtubule-based motor protein KIF13A. The precise function of FYVE-CENT during cytokinesis remains to be characterized, although one clue arises from the ﬁnding that TTC19, a protein that associates with FYVE-CENT and accompanies it on its translocation from the centrosome to the midbody, interacts with the ESCRT-III subunit CHMP4B [73]. This is interesting because ESCRT-III has been pro- posed to mediate the ﬁnal membrane abscission step during cytokinesis [74,75], and it is possible that TTC19, brought to the midbody by FYVE-CENT and KIF13A, may be a positive regulator of CHMP4B in cytokinesis. By analogy with its yeast counterpart Vps32 ⁄ Snf7, CHMP4B is predicted to form spiral- shaped oligomers that constrict to mediate membrane severing [76], and TTC19 might serve to control this oligomerization. PI3K-III and PtdIns3P effectors in tumour suppression The PI3K-III subunit Beclin 1 is monoallelically deleted in a large proportion of breast and ovarian cancers, and heterozygous beclin 1 knockout mice develop spontaneous mammary tumours [6]. These ﬁndings, combined with the observation that both Beclin 1 and its yeast homologue Vps30 mediate auto- phagy, suggest that Beclin 1 acts as a tumour suppres- sor because of its function in autophagy. In support of this idea, there is evidence that autophagy functions as tumour suppressor by scavenging damaged mitochon- dria and peroxisomes that would otherwise cause geno- mic instability through oxygen radical-induced DNA damage [77]. Further supporting the notion that PI3K-III acts as a tumour suppressor through its function in autophagy is the observation that two other PI3K-III accessory proteins identiﬁed as positive regulators of autophagy, UVRAG and BIF-1, are also tumour sup- pressors [5,7]. Even though these are compelling data, one obvious question arises regarding the role of PI3K-III in autophagy-mediated tumour suppression: are other autophagy regulators also tumour suppres- sors? One would expect that this would be the case but, so far, only one of the many other proteins impli- cated in autophagy regulation has been identiﬁed as a putative tumour suppressor, the protease ATG4C [78]. Because, among the more than 30 positive regulators of autophagy, three out of four identiﬁed tumour suppressors belong to the PI3K-III complex, the possibility exists that PI3K-III may mediate tumour suppression not by autophagy but by an alternative means. Given the importance of endocytosis and lysosomal downregulation of growth factor receptors in attenua- tion of mitogenic cell signalling [79], one distinct possi- bility is that PI3K-III could (at least in part) exert its tumour suppressor function through its role in endo- some fusion and endosomal receptor sorting. Although there is no direct evidence that this is the case, it is interesting to note that the PtdIns3P-binding endoso- mal fusion regulator, Rabenosyn, is a tumour suppres- sor in ﬂies [47], and the same is the case with multiple components of the ESCRT machinery that acts down- stream of PtdIns3P in the endosomal sorting of mito- genic receptors [80–83]. Arguing against this idea is the fact that Hrs, the PtdIns3P binding ESCRT-0 protein that initiates further ESCRT recruitment to mem- branes, is not a tumour suppressor in Drosophila. The recent discovery that PI3K-III regulates cytoki- nesis has offered a third possible explanation for the tumour suppressor activity of this enzyme complex [73]. Inhibition of PI3K-III activity not only causes an increased proportion of cells undergoing cytokinesis, but also an increase in bi- and multinucleate cells. Under certain conditions, tetraploidy may develop into aneuploidy, which is strongly associated with cancer. It is therefore likely that incomplete cytokinesis, as expe- rienced when PI3K-III or the PtdIns3P effector FYVE-CENT is functionally ablated, may represent a step in oncogenesis [84]. It is interesting to note that FYVE-CENT is frequently mutated in breast cancer [85,86], although it remains to be established whether this PtdIns3P effector is a genuine tumour suppressor. Conclusions and perspectives As discussed in the present review, PI3K-III may theo- retically function as a tumour suppressor via at least three different mechanisms (Fig. 3). The involvement of PI3K-III in autophagy maintains genome stability by eliminating damaged organelles that produce reac- tive oxygen species; the role of PI3K-III in endo- somal fusion and sorting ensures correct downregulation of mitogenic signalling; and the correct function of PI3K-III in cytokinesis prevents aneuploidy. Further work is required to establish which of these three processes is most important in PI3K-III-mediated tumour suppression. It can also not be excluded that PI3K-III may act as tumour suppressor by additional means. For example, SARA, a mediator of transform- ing growth factor-b signalling, requires PtdIns3P binding for its function [87], and the transforming FEBS Journal 277 (2010) 4837–4848 ª 2010 The Author Journal compilation ª 2010 FEBS 4843