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PMID: 10477752 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of cell biology ·Vol. 146 ·No. 5 ·1999-09-06 ·Pages 967-80

Espada J, Pérez-Moreno M, Braga VM, Rodriguez-Viciana P, Cano A

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.

MeSH Terms
Adenomatous Polyposis Coli Protein Animals Cadherins/metabolism Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Line Cell Membrane/metabolism Cell Nucleus/metabolism Cell Transformation, Neoplastic Cytoplasm/metabolism Cytoskeletal Proteins/metabolism Enzyme Activation Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Keratinocytes/cytology,enzymology,metabolism Mice Microinjections Oncogene Protein p21(ras)/genetics,metabolism Phosphatidylinositol 3-Kinases/chemistry,genetics,metabolism Phosphoinositide-3 Kinase Inhibitors Phosphorylation Phosphoserine/analysis,metabolism Phosphotyrosine/analysis Protein Binding Trans-Activators alpha Catenin beta Catenin
Chemicals
Adenomatous Polyposis Coli Protein CTNNB1 protein, mouse Cadherins Ctnna1 protein, mouse Cytoskeletal Proteins Phosphoinositide-3 Kinase Inhibitors Trans-Activators alpha Catenin beta Catenin Phosphoserine Phosphotyrosine Glycogen Synthase Kinases Calcium-Calmodulin-Dependent Protein Kinases Glycogen Synthase Kinase 3 Oncogene Protein p21(ras)
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Espada J
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28029 Madrid, Spain.
Pérez-Moreno M
Braga V M
Rodriguez-Viciana P
Cano A
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.146.5.967
Published
1999-09-06
Pages
967-80
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2169475
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.146.5.967 PMC Full Text View journal details
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