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Molecular and Cellular Biology, May 2009, p. 2359-2371, Vol. 29, No. 9
0270-7306/09/$08.00+0     doi:10.1128/MCB.01259-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Polycystin-1 Regulates Extracellular Signal-Regulated Kinase-Dependent Phosphorylation of Tuberin To Control Cell Size through mTOR and Its Downstream Effectors S6K and 4EBP1 {triangledown}

Gianfranco Distefano,1 Manila Boca,1 Isaline Rowe,1 Claas Wodarczyk,1 Li Ma,2 Klaus B. Piontek,3 Gregory G. Germino,3 Pier Paolo Pandolfi,4,5 and Alessandra Boletta1*

Dulbecco Telethon Institute at Dibit-San Raffaele, Milan, Italy,1 Whitehead Institute for Biomedical Research, Cambridge, Massachusetts,2 The Johns Hopkins University School of Medicine, Baltimore, Maryland,3 Harvard Medical School, Boston, Massachusetts,4 Beth Israel Deaconess Medical Center, Boston, Massachusetts5

Received 8 August 2008/ Returned for modification 12 August 2008/ Accepted 6 February 2009

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease characterized by bilateral renal cyst formation. Both hyperproliferation and hypertrophy have been previously observed in ADPKD kidneys. Polycystin-1 (PC-1), a large orphan receptor encoded by the PKD1 gene and mutated in 85% of all cases, is able to inhibit proliferation and apoptosis. Here we show that overexpression of PC-1 in renal epithelial cells inhibits cell growth (size) in a cell cycle-independent manner due to the downregulation of mTOR, S6K1, and 4EBP1. Upregulation of the same pathway leads to increased cell size, as found in mouse embryonic fibroblasts derived from Pkd1–/– mice. We show that PC-1 controls the mTOR pathway in a Tsc2-dependent manner, by inhibiting the extracellular signal-regulated kinase (ERK)-mediated phosphorylation of tuberin in Ser664. We provide a detailed molecular mechanism by which PC-1 can inhibit the mTOR pathway and regulate cell size.

* Corresponding author. Mailing address: Dulbecco Telethon Institute at Dibit-San Raffaele, Via Olgettina 58, 20132 Milan, Italy. Phone: 39-02 2643 4805. Fax: 39-02 2643 4861. E-mail: boletta.alessandra{at}hsr.it

{triangledown} Published ahead of print on 2 March 2009.

Molecular and Cellular Biology, May 2009, p. 2359-2371, Vol. 29, No. 9
0270-7306/09/$08.00+0     doi:10.1128/MCB.01259-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zhou, J., Brugarolas, J., Parada, L. F. (2009). Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1. Hum Mol Genet 18: 4428-4441 [Abstract] [Full Text]  


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