TY - JOUR
T1 - mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division
AU - Bonucci, Martina
AU - Kuperwasser, Nicolas
AU - Barbe, Serena
AU - Koka, Vonda
AU - de Villeneuve, Delphine
AU - Zhang, Chi
AU - Srivastava, Nishit
AU - Jia, Xiaoying
AU - Stokes, Matthew P.
AU - Bienaimé, Frank
AU - Verkarre, Virginie
AU - Lopez, Jean Baptiste
AU - Jaulin, Fanny
AU - Pontoglio, Marco
AU - Terzi, Fabiola
AU - Delaval, Benedicte
AU - Piel, Matthieu
AU - Pende, Mario
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85086781722&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-16978-z
DO - 10.1038/s41467-020-16978-z
M3 - Article
C2 - 32581239
AN - SCOPUS:85086781722
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3200
ER -