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H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes.

Title: H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes.
Authors: Espada, J
Pérez-Moreno, M
Braga, VM
Rodriguez-Viciana, P
Cano, A
Item Type: Journal Article
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.
Issue Date: 6-Sep-1999
Date of Acceptance: 3-Aug-1999
URI: http://hdl.handle.net/10044/1/62118
DOI: https://dx.doi.org/10.1083/jcb.146.5.967
ISSN: 0021-9525
Publisher: Rockefeller University Press
Start Page: 967
End Page: 980
Journal / Book Title: Journal of Cell Biology
Volume: 146
Issue: 5
Copyright Statement: © 1999 The Rockefeller University Press
Keywords: Adenomatous Polyposis Coli Protein
Calcium-Calmodulin-Dependent Protein Kinases
Cell Line
Cell Membrane
Cell Nucleus
Cell Transformation, Neoplastic
Cytoskeletal Proteins
Enzyme Activation
Glycogen Synthase Kinase 3
Glycogen Synthase Kinases
Oncogene Protein p21(ras)
Phosphatidylinositol 3-Kinases
Protein Binding
alpha Catenin
beta Catenin
06 Biological Sciences
11 Medical And Health Sciences
Developmental Biology
Publication Status: Published
Conference Place: United States
Online Publication Date: 1999-09-06
Appears in Collections:National Heart and Lung Institute