beta-catenin is a target for the ubiquitin-proteasome pathway
beta-catenin is a target for the ubiquitin-proteasome pathway
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DOI：
10.1093/emboj/16.13.3797
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发表时间：
1997-07-01
期刊：
影响因子：
11.4
通讯作者：
Kemler, R
中科院分区：
文献类型：
--
作者：
Aberle, H;Bauer, A;Kemler, R
β-连环蛋白是钙粘蛋白细胞粘附复合物的中心成分，在无翼/Wnt信号通路中起重要作用。在该途径的当前模型中，β-连环蛋白（或其无脊椎动物同系物Armadillo）的量受到严格调节，并且在无翼/Wnt信号的情况下，其在钙粘蛋白-连环蛋白复合物外的稳态水平较低。在这里，我们表明，泛素依赖的蛋白水解系统参与β-连环蛋白营业额的调节。当蛋白酶体介导的蛋白水解被抑制时，β-连环蛋白而不是E-钙粘蛋白、p120（cas）或α-连环蛋白变得稳定，这导致β-连环蛋白的多泛素化形式的积累。突变实验表明，β-连环蛋白的糖原合成酶激酶3 β（GSK 3 β）磷酸化共有基序中丝氨酸残基的取代抑制泛素化，并导致蛋白质的稳定。β-连环蛋白中的这种基序类似于I κ B（NF κ B抑制剂）中的蛾，I κ B是通过泛素-蛋白酶体途径磷酸化依赖性降解I κ B所必需的。我们表明，在Wnt表达细胞中，β-连环蛋白的泛素化大大减少，提供了第一个证据，即泛素-蛋白酶体降解途径可能在β-连环蛋白的调节中作用于GSK 3 β的下游。
beta-catenin is a central component of the cadherin cell adhesion complex and plays an essential role in the Wingless/Wnt signaling pathway. In the current model of this pathway, the amount of beta-catenin (or its invertebrate homolog Armadillo) is tightly regulated and its steady-state level outside the cadherin-catenin complex is low in the absence of Wingless/Wnt signal. Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. Mutagenesis experiments demonstrate that substitution of the serine residues in the glycogen synthase kinase 3 beta (GSK3 beta) phosphorylation consensus motif of beta-catenin inhibits ubiquitination and results in stabilization of the protein. This motif in beta-catenin resembles a moth in I kappa B (inhibitor of NF kappa B) which is required for the phosphorylation-dependent degradation of I kappa B via the ubiquitin-proteasome pathway, We show that ubiquitination of beta-catenin is greatly reduced in Wnt-expressing cells, providing the first evidence that the ubiquitin-proteasome degradation pathway may act downstream of GSK3 beta in the regulation of beta-catenin.