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

• Published in: Nature communications 2020-06, Vol.11 (1), p.3200-3200, Article 3200
• Main Authors: Bonucci, Martina, Kuperwasser, Nicolas, Barbe, Serena, Koka, Vonda, de Villeneuve, Delphine, Zhang, Chi, Srivastava, Nishit, Jia, Xiaoying, Stokes, Matthew P., Bienaimé, Frank, Verkarre, Virginie, Lopez, Jean Baptiste, Jaulin, Fanny, Pontoglio, Marco, Terzi, Fabiola, Delaval, Benedicte, Piel, Matthieu, Pende, Mario
• Format: Article
• Language: English
• Subjects: 14; 14/19; 631/80/304; 631/80/641; 631/80/86; 96; 96/95; Animals; Cell activation; Cell Division; Cell junctions; Cell Line; Cysts; E-cadherin; Genetic disorders; Humanities and Social Sciences; Hyperactivity; Kidneys; Kinases; Kinesin - genetics; Kinesin - metabolism; Life Sciences; Mass spectrometry; Mass spectroscopy; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; Mice, Mutant Strains; multidisciplinary; Mutants; Mutation; Myosins - genetics; Myosins - metabolism; Phosphorylation; Polycystic kidney; Polycystic Kidney Diseases - genetics; Polycystic Kidney Diseases - metabolism; Polycystic Kidney Diseases - pathology; Ribosomal Protein S6 Kinases, 90-kDa - genetics; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Science; Science (multidisciplinary); Signal Transduction; Substrates; TOR protein; Tuberous sclerosis; Tuberous Sclerosis - genetics; Tuberous Sclerosis - metabolism; Tuberous Sclerosis - pathology; Tuberous Sclerosis Complex 1; Tuberous Sclerosis Complex 1 Protein - genetics; Tuberous Sclerosis Complex 1 Protein - metabolism; α-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16978-z

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. mTOR activation is known to generate polycystic kidneys, which show both increased proliferation and loss of oriented cell division (OCD). Here, Bonucci et al. show that loss of OCD is linked to S6K1 activation through its direct target Afadin and is separable from hyperproliferation.