Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon

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Abstract
A balance between self-renewal and differentiation is fundamental to stem cell and cancer biology. Drosophila neural stem cells achieve this through asymmetric cell division, during which factors influencing self-renewal and differentiation are unequally segregated. Wang et al. now show that the mitotic kinase Polo regulates the asymmetric localization of the tumour-suppressor protein Numb by phosphorylating Pon, the adaptor protein for Numb. Polo acts as a tumour suppressor by regulating Pon/Numb. These findings demonstrate a direct biochemical link between the cell cycle and asymmetric protein localization, and reveal a novel tumour suppressor mechanism. The mitotic kinase Polo regulates the asymmetric localization of the tumour-suppressor protein Numb through phosphorylating Pon, the adaptor protein for Numb, and Polo acts as a tumour-suppressor through regulating Pon/Numb. This provides the first direct biochemical link between the cell cycle and asymmetric protein localization machinery and reveals a novel mechanism underlying the tumour suppressor function of Polo. Self-renewal and differentiation are cardinal features of stem cells. Asymmetric cell division provides one fundamental mechanism by which stem cell self-renewal and differentiation are balanced1,2. A failure of this balance could lead to diseases such as cancer3,4,5,6. During asymmetric division of stem cells, factors controlling their self-renewal and differentiation are unequally segregated between daughter cells. Numb is one such factor that is segregated to the differentiating daughter cell during the stem-cell-like neuroblast divisions in Drosophila melanogaster7, where it inhibits self-renewal8,9. The localization and function of Numb is cell-cycle-dependent7,10,11,12. Here we show that Polo (ref. 13), a key cell cycle regulator, the mammalian counterparts of which have been implicated as oncogenes as well as tumour suppressors14,15, acts as a tumour suppressor in the larval brain. Supernumerary neuroblasts are produced at the expense of neurons in polo mutants. Polo directly phosphorylates Partner of Numb (Pon, ref. 16), an adaptor protein for Numb, and this phosphorylation event is important for Pon to localize Numb. In polo mutants, the asymmetric localization of Pon, Numb and atypical protein kinase C are disrupted, whereas other polarity markers are largely unaffected. Overexpression of Numb suppresses neuroblast overproliferation caused by polo mutations, suggesting that Numb has a major role in mediating this effect of Polo. Our results reveal a biochemical link between the cell cycle and the asymmetric protein localization machinery, and indicate that Polo can inhibit progenitor self-renewal by regulating the localization and function of Numb.