Phosphorylation of β-catenin by cyclic AMP-dependent protein kinase stabilizes β-catenin through inhibition of its ubiquitination
Phosphorylation of β-catenin by cyclic AMP-dependent protein kinase stabilizes β-catenin through inhibition of its ubiquitination
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DOI：
10.1128/mcb.25.20.9063-9072.2005
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发表时间：
2005-10-01
影响因子：
5.3
通讯作者：
Kikuchi, A
中科院分区：
文献类型：
--
作者：
Hino, S;Tanji, C;Kikuchi, A
研究了Wnt信号与环AMP （cAMP）依赖性蛋白激酶（protein kinase A [PKA]）信号通路之间的串扰机制。前列腺素E-1 （PGE(1)）、异丙肾上腺素（isoproterenol）和二丁基cAMP （Bt(2)cAMP）均能激活PKA，增加细胞质和细胞核p -连环蛋白水平，这些作用被PKA抑制剂和RNA干扰PKA抑制。PGE(1)和Bt(2)cAMP也通过β -catenin增加t细胞因子（Tcf）依赖性转录。Bt(2)cAMP在蛋白水平上抑制β -连环蛋白的降解。尽管PKA不影响糖原合成酶激酶3 β (GSK-3 β)、β -连环蛋白和轴蛋白之间复合物的形成，但PKA对β -连环蛋白的磷酸化抑制了β -连环蛋白在完整细胞和体外的泛素化。Ser675被发现是PKA磷酸化的位点，在β -连环蛋白中用丙氨酸取代这一丝氨酸残基减弱了PKA对β -连环蛋白泛素化的抑制，PKA诱导的β -连环蛋白稳定，以及PKA依赖的Tcf激活。这些结果表明，PKA通过磷酸化β -catenin抑制β -catenin的泛素化，从而导致β -catenin积累，激活Wnt信号通路。
The mechanism of cross talk between the Wnt signaling and cyclic AMP (cAMP)-dependent protein kinase (protein kinase A [PKA]) pathways was studied. Prostaglandin E-1 (PGE(1)), isoproterenol, and dibutyryl cAMP (Bt(2)cAMP), all of which activate PKA, increased the cytoplasmic and nuclear P-catenin protein level, and these actions were suppressed by a PKA inhibitor and RNA interference for PKA. PGE(1) and Bt(2)cAMP also increased T-cell factor (Tcf)-dependent transcription through beta-catenin. Bt(2)cAMP suppressed degradation of beta-catenin at the protein level. Although PKA did not affect the formation of a complex between glycogen synthase kinase 3 beta (GSK-3 beta), beta-catenin, and Axin, phosphorylation of beta-catenin by PKA inhibited ubiquitination of beta-catenin in intact cells and in vitro. Ser675 was found to be a site for phosphorylation by PKA, and substitution of this serine residue with alanine in beta-catenin attenuated inhibition of the ubiquitination of beta-catenin by PKA, PKA-induced stabilization of beta-catenin, and PKA-dependent activation of Tcf. These results indicate that PKA inhibits the ubiquitination of beta-catenin by phosphorylating beta-catenin, thereby causing beta-catenin to accumulate and the Wnt signaling pathway to be activated.