The mechanisms controlling degradation of cytosolic β-catenin are important for regulating β-catenin co-transcriptional activity. Loss of von Hippel–Lindau protein (pVHL) has been shown to stabilize β-catenin, increasing β-catenin transactivation and β-catenin-mediated cell proliferation. However, the role of phosphoinositide 3-kinase (PI3K)/Akt in the regulation of β-catenin signaling downstream from pVHL has never been addressed. Here, we report that hyperactivation of PI3K/Akt in cells lacking pVHL contributes to the stabilization and nuclear accumulation of active β-catenin. PI3K/Akt hyperactivation is facilitated by the up-regulation of 14-3-3ζ and the down-regulation of 14-3-3ε, 14-3-3η and 14-3-3θ. Up-regulation of 14-3-3ζ in response to pVHL is important for the recruitment of PI3K to the cell membrane and for stabilization of soluble β-catenin. In contrast, 14-3-3ε and 14-3-3η enhanced PI3K/Akt signaling by inhibiting PI3K and PDK1, respectively. Thus, our results demonstrated that 14-3-3 family members enhance PI3K/Akt/β-catenin signaling in order to increase proliferation. Inhibition of Akt activation and/or 14-3-3 function strongly reduces β-catenin signaling and decreases cell proliferation. Thus, inhibition of Akt and 14-3-3 function efficiently reduces cell proliferation in 786-0 cells characterized by hyperactivation of β-catenin signaling due to pVHL loss.
pVHL suppresses Akt/β-catenin-mediated cell proliferation by inhibiting 14-3-3ζ expression
- Views Icon Views
- Share Icon Share
- Cite Icon Cite
Azucena Castañeda, Carolina Serrano, José Antonio Hernández-Trejo, Itzel Zenidel Gutiérrez-Martínez, Wilber Montejo-López, Mauricio Gómez-Suárez, Marcela Hernández-Ruiz, Abigail Betanzos, Aurora Candelario-Martínez, Hector Romo-Parra, José Antonio Arias-Montaño, Michael Schnoor, Marco Antonio Meraz Ríos, Maria Eugenia Gutierrez-Castillo, Irma Alicia Martínez-Dávila, Nicolás Villegas-Sepúlveda, Daniel Martinez-Fong, Porfirio Nava; pVHL suppresses Akt/β-catenin-mediated cell proliferation by inhibiting 14-3-3ζ expression. Biochem J 15 August 2017; 474 (16): 2679–2689. doi: https://doi.org/10.1042/BCJ20161097
Download citation file: