Direct metabolic regulation of beta-catenin activity by the p85alpha regulatory subunit of phosphoinositide 3-OH kinase.
Class IA phosphoinositide 3-OH kinases (PI3K) are lipid kinases composed of catalytic and regulatory subunits. These lipid kinases can regulate the metabolic stability and signaling activity of beta-catenin, a central component of the E-cadherin/catenin cell-cell adhesion complex, and of the Wnt signaling pathway. This regulation occurs at the level of glycogen synthase kinase 3 (GSK3), a serine/threonine kinase that marks beta-catenin to enter a destruction pathway. In addition, the regulatory subunit p85alpha directly binds beta-catenin, but the role of this interaction in the context of the lipid kinase regulation of beta-catenin signaling is unknown. Here we report that expression of exogenous p85alpha in mouse keratinocytes increases the metabolic stability and has a strong synergistic effect on the transcriptional activity of beta-catenin. Both effects are associated to the formation of beta-catenin/p85alpha and inhibition of beta-catenin/APC complexes and are independent of GSK3 and PI3K activities. These findings suggest that p85alpha can act as a direct metabolic regulator of beta-catenin activity.
Espada
Jesús
J
Centro Nacional de Investigaciones Oncológicas, Instituto de Salud Carlos III, Melchor-Fernández Almagro 3, 28029 Madrid, Spain.
Peinado
Héctor
H
Esteller
Manel
M
Cano
Amparo
A
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex