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© The Rockefeller University Press, 0021-9525/1999//967 $5.00
The Journal of Cell Biology, Volume 146, Number 5, , 1999 967-980

Original Article

H-Ras Activation Promotes Cytoplasmic Accumulation and Phosphoinositide 3-Oh Kinase Association of β-Catenin in Epidermal Keratinocytes



Jesús Espadaa, Mirna Pérez-Morenoa, Vania M.M. Bragab, Pablo Rodriguez-Vicianac, and Amparo Canoa

a Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28029 Madrid, Spain
b MRC Laboratory for Molecular Cell Biology, Department of Biochemistry and Molecular Biology, University College London, WC1E 6BT, London, United Kingdom
c University of California San Francisco Cancer Research Institute, San Francisco, California 94115
Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier, 4, 28029 Madrid, Spain.34-91-585-458734-91-585-4597

acano{at}iib.uam.es

The mechanisms underlying downregulation of the cadherin/catenin complexes and β-catenin signaling during tumor progression are not fully understood. We have analyzed the effect of oncogenic H-Ras on E-cadherin/catenin complex formation/stabilization and β-catenin distribution in epidermal keratinocytes. Microinjection or stable expression of V12Ras into keratinocytes promotes the loss of E-cadherin and {alpha}-catenin and relocalization of β-catenin to the cytoplasm and nucleus. Moreover, these effects are dependent on PI3K (phosphoinositide 3-OH kinase) activity. Interestingly, a strong association of p85{alpha} and p110{alpha} subunits of PI3K with β-catenin is induced in V12Ras-expressing keratinocytes, and in vitro binding assays show a direct interaction between β-catenin and p85{alpha}. Overexpression of either V12Ras or constitutively active p110{alpha} induces metabolic stabilization of β-catenin and promotes its accumulation in cytoplasmic and nuclear pools. In addition, the interaction of β-catenin with the adenomatous polyposis coli protein is blocked in V12Ras and p110{alpha} transformants though no changes in glycogen synthase kinase 3 β activity could be detected. Nevertheless, in V12Ras transformants the in vivo phosphorylation of β-catenin in Ser residues is strongly decreased. These results indicate that H-Ras activation induces the relocalization and cytoplasmic stabilization of β-catenin by a mechanism involving its interaction with PI3K.

Key Words: H-Ras • E-cadherin • β-catenin • adenomatous polyposis coli • phosphoinositide 3-OH • kinase

© 1999 The Rockefeller University Press

1.used in this paper: APC, adenomatous polyposis coli; GST, glutathione-S-transferase; GSK3β, glycogen synthase kinase 3β; H-Ras, Harvey-Ras; Lef-1/Tcf, lymphocyte enhancer factor 1/T cell factor; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-OH kinase; PP2A, protein phosphatase 2A


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