H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes.
The mechanisms underlying downregulation of the cadherin/catenin complexes and beta-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 beta-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 beta-catenin to the cytoplasm and nucleus. Moreover, these effects are dependent on PI3K (phosphoinositide 3-OH kinase) activity. Interestingly, a strong association of p85alpha and p110alpha subunits of PI3K with beta-catenin is induced in V12Ras-expressing keratinocytes, and in vitro binding assays show a direct interaction between beta-catenin and p85alpha. Overexpression of either V12Ras or constitutively active p110alpha induces metabolic stabilization of beta-catenin and promotes its accumulation in cytoplasmic and nuclear pools. In addition, the interaction of beta-catenin with the adenomatous polyposis coli protein is blocked in V12Ras and p110alpha transformants though no changes in glycogen synthase kinase 3 beta activity could be detected. Nevertheless, in V12Ras transformants the in vivo phosphorylation of beta-catenin in Ser residues is strongly decreased. These results indicate that H-Ras activation induces the relocalization and cytoplasmic stabilization of beta-catenin by a mechanism involving its interaction with PI3K.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Adenomatous Polyposis Coli Protein, Animals, Cadherins, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cell Membrane, Cell Nucleus, Cell Transformation, Neoplastic, Cytoplasm, Cytoskeletal Proteins, Enzyme Activation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Keratinocytes, Mice, Microinjections, Oncogene Protein p21(ras), Phosphorylation, Phosphoserine, Phosphotyrosine, Protein Binding, Trans-Activators, alpha Catenin, beta Catenin
1-Phosphatidylinositol 3-Kinase, Adenomatous Polyposis Coli Protein, Animals, Cadherins, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cell Membrane, Cell Nucleus, Cell Transformation, Neoplastic, Cytoplasm, Cytoskeletal Proteins, Enzyme Activation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Keratinocytes, Mice, Microinjections, Oncogene Protein p21(ras), Phosphorylation, Phosphoserine, Phosphotyrosine, Protein Binding, Trans-Activators, alpha Catenin, beta Catenin
J. Cell Biol.
Date: Sep. 06, 1999
PubMed ID: 10477752
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