Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism
Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism
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DOI：
10.1016/s0092-8674(02)00685-2
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发表时间：
2002-03-22
期刊：
影响因子：
64.5
通讯作者：
He, X
中科院分区：
文献类型：
--
作者：
Liu, CM;Li, YM;He, X
β-连环蛋白降解的令状调节对于发育和致癌作用至关重要。 β-连环蛋白降解是在氨基末端丝氨酸/苏氨酸磷酸化时启动的，这被认为是由糖原合酶激酶 3 (GSK-3) 与肿瘤抑制蛋白 Axin 和腺瘤性息肉病大肠杆菌 (APC) 复合进行的。在这里，我们描述了另一种轴蛋白相关激酶，其 β-连环蛋白的磷酸化先于随后的 GSK-3 β-连环蛋白的磷酸化，并且是随后的 GSK-3 磷酸化所必需的。这种“启动”激酶是酪蛋白激酶 1α (CK1α)。 CK1α 的缺失会抑制 β-连环蛋白磷酸化和降解，并导致与过度 Wnt/β-连环蛋白信号传导相关的异常胚胎发生。我们的研究揭示了 β-连环蛋白磷酸化的独特作用和步骤，确定 CK1α 作为 Wnt/β-连环蛋白信号传导的一个组成部分，并对人类癌症和糖尿病的发病机制/治疗具有影响。
Writ regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). Here we describe another Axin-associated kinase, whose phosphorylation of beta-catenin precedes and is required for subsequent GSK-3 phosphorylation of beta-catenin. This "priming" kinase is casein kinase 1alpha (CK1alpha). Depletion of CK1alpha inhibits beta-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/beta-catenin signaling. Our study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CK1alpha as a component in Wnt/beta-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.