Phosphorylation of β-catenin by cyclic AMP-dependent protein kinase
Phosphorylation of β-catenin by cyclic AMP-dependent protein kinase
复制标题
DOI：
10.1074/jbc.m508778200
复制
发表时间：
2006-04-14
影响因子：
4.8
通讯作者：
Dulin, NO
中科院分区：
文献类型：
--
作者：
Taurin, S;Sandbo, N;Dulin, NO
β-连环蛋白是一种信号分子，通过激活T细胞因子（TCF）/淋巴增强因子（LEF）转录因子诱导基因转录来促进细胞增殖。β-连环蛋白调节的经典机制涉及其在Ser-45位点被酪蛋白激酶1磷酸化以及在Thr-41、Ser-37和Ser-33位点被糖原合成酶激酶3（GSK 3）磷酸化。这种磷酸化靶向β-连环蛋白，使其被蛋白酶体系统泛素化和降解。促有丝分裂因子通过抑制GSK 3促进β-连环蛋白信号传导，导致β-连环蛋白磷酸化减少、其稳定化以及随后在细胞核中的积累，在细胞核中其刺激TCF/LEF依赖性基因转录。在本研究中，我们发现：（i）在体外和完整细胞中，蛋白激酶A（PKA）可以在两个新位点Ser-552和Ser-675磷酸化β-catenin;（ii）PKA磷酸化促进转录活性，（iii）Ser-675突变减弱PKA的促进作用;（iv）PKA的磷酸化不影响β-连环蛋白的GSK 3依赖性磷酸化、其稳定性或细胞内定位;和（v）Ser-675位点的磷酸化促进β-连环蛋白与其转录辅激活因子CREB结合蛋白的结合。总之，这项研究确定了一种新的，非经典的β-连环蛋白信号转导的调制机制，通过PKA直接磷酸化β-连环蛋白，促进其与CREB结合蛋白的相互作用。
beta-Catenin is a signaling molecule that promotes cell proliferation by the induction of gene transcription through the activation of T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription factors. The canonical mechanism of the regulation of beta-catenin involves its phosphorylation by casein kinase 1 at the Ser-45 site and by glycogen synthase kinase 3 (GSK3) at the Thr-41, Ser-37, and Ser-33 sites. This phosphorylation targets beta-catenin to ubiquitination and degradation by the proteasome system. Mitogenic factors promote beta-catenin signaling through the inhibition of GSK3, resulting in reduced beta-catenin phosphorylation, its stabilization, and subsequent accumulation in the nucleus, where it stimulates TCF/LEF-dependent gene transcription. In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase A (PKA) in vitro and in intact cells at two novel sites, Ser-552 and Ser-675; (ii) phosphorylation by PKA promotes the transcriptional activity (TCF/LEF transactivation) of beta-catenin; (iii) mutation of Ser-675 attenuates the promoting effect of PKA; (iv) phosphorylation by PKA does not affect the GSK3-dependent phosphorylation of beta-catenin, its stability, or intracellular localization; and ( v) phosphorylation at the Ser-675 site promotes the binding of beta-catenin to its transcriptional coactivator, CREB-binding protein. In conclusion, this study identifies a novel, noncanonical mechanism of modulation of beta-catenin signaling through direct phosphorylation of beta-catenin by PKA, promoting its interaction with CREB-binding protein.