Editors' ChoiceMechanotransduction

Flow into a New Cell Size

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Science Signaling  16 Nov 2010:
Vol. 3, Issue 148, pp. ec347
DOI: 10.1126/scisignal.3148ec347

Mutations in genes encoding proteins involved in cilia formation, such as the kinesin subunit Kif3a or the intraflagellar transport protein Ift88, result in various developmental defects and diseases, such as polycystic kidney disease (PKD). In PKD, kidneys contain cysts, and the cells lining the cysts are larger and have increased mTORC1 (mammalian target of rapamycin complex 1) activity compared with normal tubular cells. Because mTORC1-mediated signaling regulates cell size, Boehlke et al. (see also Wiczer et al.) investigated the relationship between cilia, fluid flow, mTORC1, and cell size. Cilia are lost in mice with a kidney-specific ablation of Kif3a, leading to formation of kidney cysts, and the authors showed that the collecting duct cells in Kif3a­ mutant mice were larger than those from control mice. MDCK cells cultured under constant flow (to mimic the conditions that renal tubule cells experience) were smaller than those grown in stationary culture. In MDCK cells cultured under constant flow, knockdown of Kif3a or of Ift88 increased cell size. mTORC1 activity, as assessed by the phosphorylation status of mTOR and its target S6K, was decreased in cells grown under constant flow compared with those grown in stationary culture, and this decrease was reduced by knockdown of Kif3a or Ift88. Furthermore, phosphorylation of the S6K target ribosomal S6 protein (rS6) was higher in kidneys from Kif3a mutants than in those from control animals. The authors reasoned that cells lacking cilia cannot sense flow and decrease mTORC1 activity, resulting in increased cell size. Accordingly, inhibition of mTORC1 with rapamycin prevented the size increase seen in cells lacking Kif3a, whereas activation of mTORC1 with expression of a gain-of-function form of Rheb (an activator of mTORC1) resulted in larger cells under flow. The kinase LKB1 activates adenosine monophosphate (AMP)–activated protein kinase (AMPK), which inhibits signaling through mTORC1. When grown under flow, MDCK cells lacking LKB1 or expressing a dominant-negative form of LKB1 were larger. In addition, imaging indicated a stronger signal for phosphorylated AMPK at the basal body in cells grown under flow than in cells grown in stationary medium. Thus, fluid flow activates the LKB1-AMPK pathway in cilia to inhibit mTORC1-mediated increases in cell size.

C. Boehlke, F. Kotsis, V. Patel, S. Braeg, H. Voelker, S. Bredt, T. Beyer, H. Janusch, C. Hamann, M. Gödel, K. Müller, M. Herbst, M. Hornung, M. Doerken, M. Köttgen, R. Nitschke, P. Igarashi, G. Walz, E. W. Kuehn, Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat. Cell Biol. 12, 1115–1122 (2010). [PubMed]

B. M. Wiczer, A. Kalender, G. Thomas, Bending the path to TOR. Nat. Cell Biol. 12, 1031–1033 (2010). [PubMed]

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