Abstract
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.
| Original language | English |
|---|---|
| Journal | Journal of Cell Biology |
| Volume | 146 |
| Issue number | 5 |
| Pages (from-to) | 967-80 |
| Number of pages | 14 |
| ISSN | 0021-9525 |
| Publication status | Published - 6 Sept 1999 |
Keywords
- 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)
- Phosphatidylinositol 3-Kinases
- Phosphorylation
- Phosphoserine
- Phosphotyrosine
- Protein Binding
- Trans-Activators
- alpha Catenin
- beta Catenin
- Journal Article
- Research Support, Non-U.S. Gov't