mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division.
Martina BonucciNicolas KuperwasserSerena BarbeVonda KokaDelphine de VilleneuveChi ZhangNishit SrivastavaXiaoying JiaMatthew P StokesFrank BienaiméVirginie VerkarreJean Baptiste LopezFanny JaulinMarco PontoglioFabiola TerziBenedicte DelavalMatthieu PielMario PendePublished in: Nature communications (2020)
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.
Keyphrases
- single cell
- cell therapy
- mass spectrometry
- cell proliferation
- induced apoptosis
- gene expression
- machine learning
- stem cells
- obsessive compulsive disorder
- epithelial mesenchymal transition
- cell cycle arrest
- mesenchymal stem cells
- big data
- electronic health record
- cell death
- genome wide
- artificial intelligence
- pi k akt
- single molecule
- cell adhesion