Primary cilia regulate mTORC1 activity and cell size through Lkb1

Christopher Boehlke, Fruzsina Kotsis, Vishal Patel, Simone Braeg, Henriette Voelker, Saskia Bredt, Theresa Beyer, Heike Janusch, Christoph Hamann, Markus Gödel, Klaus Müller, Martin Herbst, Miriam Hornung, Mara Doerken, Michael Köttgen, Roland Nitschke, Peter Igarashi, Gerd Walz, E. Wolfgang Kuehn

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218 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1115-1122
Number of pages8
JournalNature Cell Biology
Volume12
Issue number11
DOIs
Publication statusPublished - Nov 2010

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Boehlke, C., Kotsis, F., Patel, V., Braeg, S., Voelker, H., Bredt, S., ... Kuehn, E. W. (2010). Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nature Cell Biology, 12(11), 1115-1122. https://doi.org/10.1038/ncb2117