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© The Rockefeller University Press, 0021-9525/1999/9/967/ $5.00
The Journal of Cell Biology, Volume 146, Number 5, September 6, 1999 967-980

H-Ras Activation Promotes Cytoplasmic Accumulation and Phosphoinositide 3-OH Kinase Association of ß-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

Correspondence to: Amparo Cano, Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier, 4, 28029 Madrid, Spain. Tel:34-91-585-4597 Fax:34-91-585-4587 E-mail:acano{at}iib.uam.es.

The mechanisms underlying downregulation of the cadherin/catenin complexes and ß-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 ß-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 ß-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 ß-catenin is induced in V12Ras-expressing keratinocytes, and in vitro binding assays show a direct interaction between ß-catenin and p85{alpha}. Overexpression of either V12Ras or constitutively active p110{alpha} induces metabolic stabilization of ß-catenin and promotes its accumulation in cytoplasmic and nuclear pools. In addition, the interaction of ß-catenin with the adenomatous polyposis coli protein is blocked in V12Ras and p110{alpha} transformants though no changes in glycogen synthase kinase 3 ß activity could be detected. Nevertheless, in V12Ras transformants the in vivo phosphorylation of ß-catenin in Ser residues is strongly decreased. These results indicate that H-Ras activation induces the relocalization and cytoplasmic stabilization of ß-catenin by a mechanism involving its interaction with PI3K.

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


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