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.

Aberrant phosphorylation inactivates Numb in breast cancer causing expansion of the stem cell pool / M.G. Filippone, S. Freddi, S. Zecchini, S. Restelli, I.N. Colaluca, G. Bertalot, S. Pece, D. Tosoni, P.P. Di Fiore. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 221:12(2022 Dec 05), pp. e202112001.1-e202112001.22, S1-S5. [10.1083/jcb.202112001]

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

M.G. Filippone
Primo
;
S. Freddi
Secondo
;
S. Zecchini;S. Restelli;S. Pece;P.P. Di Fiore
Ultimo
2022

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.
Asymmetric Cell Division; Female; Humans; Mitosis; Phosphorylation; Breast Neoplasms; Membrane Proteins; Neoplastic Stem Cells; Nerve Tissue Proteins
Settore MED/04 - Patologia Generale
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/946808
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