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H-Ras激活促进表皮角质形成细胞中β-连环蛋白的细胞质积累和磷酸肌醇3-羟基激酶结合。

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

作者信息

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

机构信息

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28029 Madrid, Spain.

出版信息

J Cell Biol. 1999 Sep 6;146(5):967-80. doi: 10.1083/jcb.146.5.967.

DOI:10.1083/jcb.146.5.967
PMID:10477752
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2169475/
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.

摘要

在肿瘤进展过程中，钙黏蛋白/连环蛋白复合体和β-连环蛋白信号下调的潜在机制尚未完全明确。我们分析了致癌性H-Ras对表皮角质形成细胞中E-钙黏蛋白/连环蛋白复合体形成/稳定性及β-连环蛋白分布的影响。将V12Ras显微注射或稳定表达于角质形成细胞中，可促进E-钙黏蛋白和α-连环蛋白的丢失，并使β-连环蛋白重新定位于细胞质和细胞核。此外，这些效应依赖于PI3K（磷酸肌醇3-OH激酶）活性。有趣的是，在表达V12Ras的角质形成细胞中，PI3K的p85α和p110α亚基与β-连环蛋白强烈结合，体外结合试验显示β-连环蛋白与p85α之间存在直接相互作用。V12Ras或组成型活性p110α的过表达诱导β-连环蛋白的代谢稳定，并促进其在细胞质和细胞核池中的积累。此外，在V12Ras和p110α转化体中，β-连环蛋白与腺瘤性息肉病大肠杆菌蛋白的相互作用被阻断，尽管未检测到糖原合酶激酶3β活性的变化。然而，在V12Ras转化体中，β-连环蛋白丝氨酸残基的体内磷酸化显著降低。这些结果表明，H-Ras激活通过一种涉及其与PI3K相互作用的机制诱导β-连环蛋白的重新定位和细胞质稳定。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0655/2169475/5e4311ed9e0e/JCB9902081.f8.jpg
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