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Biochem J. 2017 Jul 27;474(16):2679-2689. doi: 10.1042/BCJ20161097.

pVHL suppresses Akt/β-catenin-mediated cell proliferation by inhibiting 14-3-3ζ expression.

Author information

1
Departamento de Fisiología, Biofísica y Neurociencias del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México DF. C.P. 07360, Mexico.
2
Departamento de Biomedicina Molecular del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México DF. C.P. 07360, Mexico.
3
Departamento de infectómica y patogénesis molecular del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México DF. C.P. 07360, Mexico.
4
Universidad Anahuac, Facultad de Psicología, Av. Universidad Anáhuac 46, Lomas Anáhuac, 52786 Naucalpan de Juárez, Mexico.
5
Departamento de Biociencias e Ingeniería, CIIEMAD-IPN, 30 de Junio de 1520 s/n, La Laguna Ticoman, México DF. C.P. 07340, Mexico.
6
Departamento de Fisiología, Biofísica y Neurociencias del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México DF. C.P. 07360, Mexico pnava@fisio.cinvestav.mx.

Abstract

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.

KEYWORDS:

14-3-3 proteins; pVHL; protein kinase B; β-catenin

PMID:
28666999
DOI:
10.1042/BCJ20161097
[Indexed for MEDLINE]

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