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

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 phosphorylation of tuberin in Ser664. We provide a detailed molecular mechanism by which PC-1 can inhibit the mTOR pathway and regulate cell size.

Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway

“…1 C and D), suggesting that the underlying mechanisms of GPR10 expression and PI3K-AKT-mTOR pathway activation in fibroids may be interrelated. Activation of AKT/mTOR and ensuing phosphorylation of the downstream targets p70S6K and 4EBP1 are known to promote cell growth and proliferation (37)(38)(39). Results from our experiments using cultured primary myometrial and leiomyoma cells confirm that the activation of GPR10 by PrRP results in the activation of PI3K/AKT-mTOR pathway, mobilization of intracellular calcium, and mitogenic responses in leiomyoma cells, revealing a unique role for GPR10 in leiomyoma cell signaling and cell proliferation.…”

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

“…We studied other signaling molecules reported to be affected in PKD that also influence mTOR activity, such as activation of Akt and ERK1/2. 27 Using Western blot analysis, low levels of p-Akt Ser473 were detected in mildly affected tissues (untreated, 80 days), which were similar upon low-and high-dose treatment ( Figure 5, A and C). The p-Akt ser473 levels increased in all groups over time.…”

Deficiency of hepatocystin induces autophagy through an mTOR-dependent pathway

“…4 Genetic defects in ADPKD lead to activation of mTOR; and the suppression of mTOR by rapamycin reduces cyst formation. 42,43 Although these studies did not examine autophagy directly, it is reasonable to assume that autophagy was induced by the rapamycin treatment and therefore might contribute to the observed therapeutic effect.…”