Aberrant phosphorylation inactivates Numb in breast cancer causing expansion of the stem cell pool

Abstract

Asymmetric cell division is a key tumor suppressor mechanism that prevents the uncontrolled expansion of the stem cell (SC) compartment by generating daughter cells with alternative fates: one retains SC identity and enters quiescence and the other becomes a rapidly proliferating and differentiating progenitor. A critical player in this process is Numb, which partitions asymmetrically at SC mitosis and inflicts different proliferative and differentiative fates in the two daughters. Here, we show that asymmetric Numb partitioning per se is insufficient for the proper control of mammary SC dynamics, with differential phosphorylation and functional inactivation of Numb in the two progeny also required. The asymmetric phosphorylation/inactivation of Numb in the progenitor is mediated by the atypical PKCζ isoform. This mechanism is subverted in breast cancer via aberrant activation of PKCs that phosphorylate Numb in both progenies, leading to symmetric division and expansion of the cancer SC compartment, associated with aggressive disease. Thus, Numb phosphorylation represents a target for breast cancer therapy.

Post-translational regulation of the Numb/Notch pathway in neurogenesis and cancer by Dlk2

“…As shown previously 4 , Numb phosphorylation did not significantly affect the level of total Numb protein in these cells (Extended Fig. 6b).…”

“…Phosphorylation of Numb has been reported to destabilize the NUMB-p53 interaction 41 and, more specifically, aberrant phosphorylation on S276 residue renders Numb inactive in breast cancer, disrupting its tumor suppressor role 4 . This specific regulation of the phosphorylation of Numb was previously shown in other developmental systems, as constitutive S276 phosphorylation prevents Numb from recycling EGFR from the apical membrane of postnatal radial glial progenitors/stem cells in postnatal subependymal zone niche development 42,43 .…”

“…Numb was recently reported to be aberrantly phosphorylated on Ser 276 (S276) in breast cancer cells 4 . We confirmed these data in both MDA-MB-231 and MCF-7 (Fig.…”

The Multitasker Protein: A Look at the Multiple Capabilities of NUMB

“…NUMB has been proposed to be involved in the regulation of multiple cellular pathways commonly altered in cancer, such as Wnt, Notch, or Hedgehog, due to its interactions with a wide variety of proteins [24][25][26][27][28]. It is also thought to be involved in the maintenance of the cancer stem cell (CSC) pool [28,29]. NUMB has also been linked to Alzheimer's disease, where it plays a role as an adaptor of amyloid precursor protein (APP), an essential protein in the pathogenesis of the disease [23].…”