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Primary cilia regulate mTORC1 activity and cell size through Lkb1
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Journal Article
Primary cilia regulate mTORC1 activity and cell size through Lkb1
2010
Overview
The mTOR pathway is a well-known regulator of cell size, and deregulation of mTOR has been observed in cilia-related diseases. Cilia modulate cell size by restricting LKB-1-mediated activation of AMPK to the basal body, which subsequently affects mTOR signalling.
The mTOR pathway is the central regulator of cell size
1
. 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
2
,
3
,
4
. Deregulation of the mTOR pathway occurs in polycystic kidney disease (PKD)
5
,
6
,
7
, where cilia (filiform sensory organelles) fail to sense urine flow because of inherited mutations in ciliary proteins
8
. 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
