Polycystin-1 regulates extracellular signal-regulated kinase-dependent phosphorylation of tuberin to control cell size through mTOR and its downstream effectors S6K and 4EBP1

Gianfranco Distefano, Manila Boca, Isaline Rowe, Claas Wodarczyk, Li Ma, Klaus B. Piontek, Gregory G. Germino, Pier Paolo Pandolfi, Alessandra Boletta

Research output: Contribution to journalArticle

Abstract

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 phosphory- lation of tuberin in Ser664. We provide a detailed molecular mechanism by which PC-1 can inhibit the mTOR pathway and regulate cell size. Copyright &copy 2009, American Society for Microbiology.

Original languageEnglish
Pages (from-to)2359-2371
Number of pages13
JournalMolecular and Cellular Biology
Volume29
Issue number9
DOIs
Publication statusPublished - May 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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