mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2020

mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division

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Nishit Srivastava
Matthieu Piel

Abstract

mTOR activation is essential and sufficient to cause polycystic kidneys in Tuberous Sclerosis Complex (TSC) and other genetic disorders. In disease models, a sharp increase of proliferation and cyst formation correlates with a dramatic loss of oriented cell division (OCD). We find that OCD distortion is intrinsically due to S6 kinase 1 (S6K1) activation. The concomitant loss of S6K1 in Tsc1-mutant mice restores OCD but does not decrease hyperproliferation, leading to non-cystic harmonious hyper growth of kidneys. Mass spectrometry-based phosphoproteomics for S6K1 substrates revealed Afadin, a known component of cell-cell junctions required to couple intercellular adhesions and cortical cues to spindle orientation. Afadin is directly phosphorylated by S6K1 and abnormally decorates the apical surface of Tsc1-mutant cells with E-cadherin and α-catenin. Our data reveal that S6K1 hyperactivity alters centrosome positioning in mitotic cells, affecting oriented cell division and promoting kidney cysts in conditions of mTOR hyperactivity.
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Dates and versions

inserm-02908117 , version 1 (28-07-2020)

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Cite

Martina Bonucci, Nicolas Kuperwasser, Serena Barbe, Vonda Koka, Delphine de Villeneuve, et al.. mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division. Nature Communications, 2020, 11 (1), pp.3200. ⟨10.1038/s41467-020-16978-z⟩. ⟨inserm-02908117⟩
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