REGULATORY MECHANISMS IMPLICATED IN THE CONTROL OF NUMB ASYMMETRIC PARTITIONING AT MITOSIS OF ADULT MAMMARY STEM CELLS

The cell fate determinant Numb has been recently shown to control the asymmetric outcome of self-renewing divisions in the normal mammary stem cell (MaSC) compartment. Loss of Numb results in the appearance of stem cells (SCs) endowed with an enhanced symmetric self-renewal ability (leading to expansion of the SC compartment) and with tumorigenic potential. The role of Numb in MaSCs is linked to its ability to asymmetrically partition at mitosis into the progeny that retains the SC identity, where it sustains the tumour suppressor activity of p53. Phosphorylation of Numb by the Par Complex (Par3/Par6/atypical PKC) is an evolutionary conserved mechanism to specify Numb asymmetric partitioning at SC mitosis. In this thesis work, we used a molecular genetics approach to demonstrate that a proper cycle of Numb phosphorylation and de-phosphorylation is essential to guarantee the asymmetric partitioning of Numb at mitosis of MaSCs. We also propose a conserved role for the atypical PKC isoenzyme and Par3 in the regulation of these events. Moreover, our preliminary data show that Numb phosphorylation mediated by aPKC impairs Numb interaction with p53, suggesting that the regulation of Numb phosphorylation can be also linked to its tumour suppressor function.