Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification.
Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification.
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DOI：
10.1083/jcb.148.4.691
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发表时间：
2000-02-21
期刊：
影响因子：
--
通讯作者：
Kimelman D
中科院分区：
文献类型：
--
作者：
Farr GH 3rd;Ferkey DM;Yost C;Pierce SB;Weaver C;Kimelman D
糖原合成酶激酶3（GSK-3）是负调节其底物的组成型活性激酶，其中之一是β-连环蛋白，其是爪蟾胚胎中背腹轴特化所需的Wnt信号通路的下游效应物。GSK-3活性通过多种蛋白质的相反活性来调节。Axin、GSK-3和β-catenin形成复合物，其促进GSK-3介导的磷酸化和随后的β-catenin降解。腺瘤性结肠息肉病（APC）加入复合物并下调哺乳动物细胞中的β-连环蛋白，但其在非洲爪蟾中的作用尚不清楚。相反，GBP，这是非洲爪蟾轴形成所需的，结合和抑制GSK-3。我们发现GSK-3结合蛋白（GBP）部分通过阻止Axin与GSK-3结合来抑制GSK-3。同样，我们提出的证据表明，一个显性负GSK-3突变体，它会导致相同的影响GBP，保持内源性GSK-3结合轴蛋白。我们表明，GBP还通过阻止GSK-3介导的蛋白质底物磷酸化而不消除其催化活性来发挥作用。最后，我们表明，先前证明的轴诱导属性的过表达APC是由于其稳定细胞质β-连环蛋白水平的能力，证明APC是在这个模型系统中的经典Wnt通路的冲击。这些结果有助于我们越来越多地了解GSK-3在早期胚胎中的调节如何导致β-catenin水平和背轴建立的区域差异。
Glycogen synthase kinase 3 (GSK-3) is a constitutively active kinase that negatively regulates its substrates, one of which is β-catenin, a downstream effector of the Wnt signaling pathway that is required for dorsal–ventral axis specification in the Xenopus embryo. GSK-3 activity is regulated through the opposing activities of multiple proteins. Axin, GSK-3, and β-catenin form a complex that promotes the GSK-3–mediated phosphorylation and subsequent degradation of β-catenin. Adenomatous polyposis coli (APC) joins the complex and downregulates β-catenin in mammalian cells, but its role in Xenopus is less clear. In contrast, GBP, which is required for axis formation in Xenopus, binds and inhibits GSK-3. We show here that GSK-3 binding protein (GBP) inhibits GSK-3, in part, by preventing Axin from binding GSK-3. Similarly, we present evidence that a dominant-negative GSK-3 mutant, which causes the same effects as GBP, keeps endogenous GSK-3 from binding to Axin. We show that GBP also functions by preventing the GSK-3–mediated phosphorylation of a protein substrate without eliminating its catalytic activity. Finally, we show that the previously demonstrated axis-inducing property of overexpressed APC is attributable to its ability to stabilize cytoplasmic β-catenin levels, demonstrating that APC is impinging upon the canonical Wnt pathway in this model system. These results contribute to our growing understanding of how GSK-3 regulation in the early embryo leads to regional differences in β-catenin levels and establishment of the dorsal axis.
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