TY - JOUR
T1 - Primary cilia regulate mTORC1 activity and cell size through Lkb1
AU - Boehlke, Christopher
AU - Kotsis, Fruzsina
AU - Patel, Vishal
AU - Braeg, Simone
AU - Voelker, Henriette
AU - Bredt, Saskia
AU - Beyer, Theresa
AU - Janusch, Heike
AU - Hamann, Christoph
AU - Gödel, Markus
AU - Müller, Klaus
AU - Herbst, Martin
AU - Hornung, Miriam
AU - Doerken, Mara
AU - Köttgen, Michael
AU - Nitschke, Roland
AU - Igarashi, Peter
AU - Walz, Gerd
AU - Kuehn, E. Wolfgang
PY - 2010/11/1
Y1 - 2010/11/1
N2 - The mTOR pathway is the central regulator of cell size. External signals from growth factors and nutrients converge on the mTORC1 multi-protein complex to modulate downstream targets, but how the different inputs are integrated and translated into specific cellular responses is incompletely understood. Deregulation of the mTOR pathway occurs in polycystic kidney disease (PKD), where cilia (filiform sensory organelles) fail to sense urine flow because of inherited mutations in ciliary proteins. We therefore investigated if cilia have a role in mTOR regulation. Here, we show that ablation of cilia in transgenic mice results in enlarged cells when compared with control animals. In vitro analysis demonstrated that bending of the cilia by flow is required for mTOR downregulation and cell-size control. Surprisingly, regulation of cell size by cilia is independent of flow-induced calcium transients, or Akt. However, the tumour-suppressor protein Lkb1 localises in the cilium, and flow results in increased AMPK phosphorylation at the basal body. Conversely, knockdown of Lkb1 prevents normal cell-size regulation under flow conditions. Our results demonstrate that the cilium regulates mTOR signalling and cell size, and identify the cilium-basal body compartment as a spatially restricted activation site for Lkb1 signalling.
AB - The mTOR pathway is the central regulator of cell size. External signals from growth factors and nutrients converge on the mTORC1 multi-protein complex to modulate downstream targets, but how the different inputs are integrated and translated into specific cellular responses is incompletely understood. Deregulation of the mTOR pathway occurs in polycystic kidney disease (PKD), where cilia (filiform sensory organelles) fail to sense urine flow because of inherited mutations in ciliary proteins. We therefore investigated if cilia have a role in mTOR regulation. Here, we show that ablation of cilia in transgenic mice results in enlarged cells when compared with control animals. In vitro analysis demonstrated that bending of the cilia by flow is required for mTOR downregulation and cell-size control. Surprisingly, regulation of cell size by cilia is independent of flow-induced calcium transients, or Akt. However, the tumour-suppressor protein Lkb1 localises in the cilium, and flow results in increased AMPK phosphorylation at the basal body. Conversely, knockdown of Lkb1 prevents normal cell-size regulation under flow conditions. Our results demonstrate that the cilium regulates mTOR signalling and cell size, and identify the cilium-basal body compartment as a spatially restricted activation site for Lkb1 signalling.
UR - http://www.scopus.com/inward/record.url?scp=78149259013&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78149259013&partnerID=8YFLogxK
U2 - 10.1038/ncb2117
DO - 10.1038/ncb2117
M3 - Article
C2 - 20972424
AN - SCOPUS:78149259013
VL - 12
SP - 1115
EP - 1122
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 11
ER -