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.