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

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Abstract
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 α-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 p85α and p110α 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 p85α. Overexpression of either V12Ras or constitutively active p110α 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 p110α 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.