CK2 phosphorylation of the armadillo repeat region of β-catenin potentiates Wnt signaling
CK2 phosphorylation of the armadillo repeat region of β-catenin potentiates Wnt signaling
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DOI：
10.1074/jbc.m212260200
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发表时间：
2003-06-27
影响因子：
4.8
通讯作者：
Seldin, DC
中科院分区：
文献类型：
--
作者：
Song, DH;Dominguez, I;Seldin, DC
蛋白激酶CK2是一种普遍存在的丝氨酸/苏氨酸激酶，参与多种生物过程。它在包括啮齿动物和人类乳腺癌在内的许多恶性肿瘤中过表达，在Wnt基因转导的乳腺上皮细胞中表达上调，在这种细胞中可以发现它与蓬乱的β-连环蛋白形成的复合体。β-连环蛋白是CK2的底物，抑制CK2会降低β-连环蛋白的水平并使其蓬乱。在这里，我们报告，使用药物抑制CK2或表达激酶失活亚基以蛋白酶体依赖的方式降低β-连环蛋白依赖的转录和蛋白质水平。CK2对β-连环素进行磷酸化的主要区域是中央螳螂重复结构域，在那里，载体蛋白如Axin和腺瘤性息肉病基因产物APC与β-连环素相互作用。CK2在这个区域的主要磷酸化位点是Thr(393)，它是分子关键铰链区的一个溶剂可及残基。这种单一氨基酸的突变降低了β-连环素的磷酸化、共转录活性和稳定性。因此，CK2通过磷酸化Thr(393)上的β-连环蛋白来正向调节Wnt信号，导致蛋白酶体抵抗，蛋白质和共转录活性增加。
Protein kinase CK2 is a ubiquitous serine/threonine kinase involved in many biological processes. It is overexpressed in many malignancies including rodent and human breast cancer, and is up-regulated in Wnt-transfected mammary epithelial cells, where it can be found in a complex with dishevelled and beta-catenin. beta-Catenin is a substrate for CK2 and inhibition of CK2 reduces levels of beta-catenin and dishevelled. Here we report that inhibition of CK2 using pharmacologic agents or expression of kinase inactive subunits reduces beta-catenin-dependent transcription and protein levels in a proteasome-dependent fashion. The major region of phosphorylation of beta-catenin by CK2 is the central armadillo repeat domain, where carrier proteins like axin and the adenomatous polyposis coli gene product APC interact with beta-catenin. The major CK2 phosphorylation site in this domain is Thr(393), a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, co-transcriptional activity, and stability. Thus, CK2 is a positive regulator of Wnt signaling through phosphorylation of beta-catenin at Thr(393), leading to proteasome resistance and increased protein and co-transcriptional activity.