Krebs medal review: PtdIns3P in tumour suppression H. Stenmark growth factor-b signalling pathway does have a tumour suppressor role under most conditions [88]. Furthermore, PtdIns3P binding subunits mediate mem- brane association of the retromer complex [89], which sorts cargoes such as mannose 6-phosphate receptors and Wntless (an accessory factor in Wnt secretion) for trafﬁcking from endosomes to the biosynthetic path- way [89,90]. Even though there is no evidence so far that implicates the retromer in tumour suppression, this possibility cannot at present be discarded. The involvement of PI3K-III in diverse cellular pro- cesses raises the question of how this complex is recruited to the correct membranes at the right time. There is evidence that PI3K-III is recruited to early and late endosomal membranes through interactions with the small GTPases RAB5 and RAB7, respectively [91–93]. Less is known about how PI3K-III is recruited to midbodies and autophagic membranes, although the latter is likely to be mediated by the autophagy-speciﬁc subunit ATG14 [69]. In addition, the ﬁnding that phosphorylation of VPS34 during mitosis causes its dissociation from Beclin 1 [18] provides a hint that post-translational modiﬁcations of PI3K-III may con- tribute to regulate its activity and speciﬁcity. Although considerable efforts have been made to understand how PtdIns3P is formed by PI3K-III, we are also beginning to learn about the metabolism of this lipid. Three known routes for PtdIns3P metabo- lism have been described: degradation by lysosomal lipases, phosphorylation by the PtdIns3P 5-kinase Fab1 ⁄ PIKfyve, and dephosphorylation by 3-phospha- tases [94]. It is worth noting that Fab1 ⁄ PIKfyve is itself a PtdIns3P binding protein [95], and that MTM1 and MTMR2, two phosphatases capable of dephosphorylating PtdIns3P, can associate with PI3K-III Fig. 3. Alternative tumour suppressor mechanisms of PI3K-III. Three alternative (hypothetic) tumour suppressor mechanisms downstream of PtdIns3P formation are shown. The relative importance of these mechanisms in the tumour suppressor activity of PI3K-III subunits remains to be established. on endosomal membranes [96,97]. This suggests a tight regulation of PtdIns3P formation and turnover, and it will be interesting to determine whether PIKfyve and MTM1 ⁄ MTMR2 may play any role in tumourigenesis. Even though it is assumed that PI3K-III functions as tumour suppressor through its ability to produce PtdIns3P at the correct intracellular membranes, this has not been formally demonstrated and, to date, we do not know whether the catalytic subunit of PI3K-III, VPS34, is a tumour suppressor. Further studies should clarify this, and it will also be important to establish whether the catalytic function of VPS34 is required for its eventual tumour suppressor function. If we nevertheless accept that PI3K-III acts as tumour suppressor through PtdIns3P generation, can this be exploited in cancer diagnosis and therapy? Because it is much easier to inhibit an enzyme phar- macologically than to boost its function, the tumour promotor PI3K-I is a more attractive drug target than the tumour suppressor PI3K-III. On the other hand, we know that PtdIns3P can be dephosphoryl- ated and that PI3K-III undergoes negative regulation [11,12], and alleviation of these inhibitory mechanisms might provide a viable strategy towards increasing the tumour suppressor activity of PI3K-III and its cata- lytic product in cancer treatment. More straightfor- wardly, knowing that PI3K-III subunits such as Beclin 1 and UVRAG are frequently downregulated or mutated in cancers [6,7,67,98,99], it will be interest- ing to perform systematic analyses of PI3K-III subun- its and key PtdIns3P effectors in various cancers. Such studies should reveal mutational and expression- based signatures that can be used to predict the outcome of disease, and to guide the choice of thera- peutic regimens. 4844 FEBS Journal 277 (2010) 4837–4848 ª 2010 The Author Journal compilation ª 2010 FEBS