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

Martina Bonucci, Nicolas Kuperwasser, Serena Barbe, Vonda Koka, Delphine Villeneuve, Chi Zhang, Nishit Srivastava, Xiaoying Jia, Matthew P. Stokes, Frank Bienaimé, Virginie Verkarre, Jean Baptiste Lopez, Fanny Jaulin, Marco Pontoglio, Fabiola Terzi, Benedicte Delaval, Matthieu Piel and Mario Pende ()
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Martina Bonucci: 14 rue Maria Helena Vieira Da Silva
Nicolas Kuperwasser: 14 rue Maria Helena Vieira Da Silva
Serena Barbe: 14 rue Maria Helena Vieira Da Silva
Vonda Koka: 14 rue Maria Helena Vieira Da Silva
Delphine Villeneuve: 14 rue Maria Helena Vieira Da Silva
Chi Zhang: 14 rue Maria Helena Vieira Da Silva
Nishit Srivastava: PSL Research University, CNRS, UMR 144
Xiaoying Jia: 3 Trask Lane
Matthew P. Stokes: 3 Trask Lane
Frank Bienaimé: 14 rue Maria Helena Vieira Da Silva
Virginie Verkarre: Equipe Labellisée par la Ligue contre le Cancer
Jean Baptiste Lopez: Gustave Roussy
Fanny Jaulin: Gustave Roussy
Marco Pontoglio: 14 rue Maria Helena Vieira Da Silva
Fabiola Terzi: 14 rue Maria Helena Vieira Da Silva
Benedicte Delaval: Univ. Montpellier, Centrosome, cilia and pathologies Lab, 1919 Route de Mende
Matthieu Piel: PSL Research University, CNRS, UMR 144
Mario Pende: 14 rue Maria Helena Vieira Da Silva

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16978-z

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