Casein kinase I and casein kinase II differentially regulate Axin function in Wnt and JNK pathways
Casein kinase I and casein kinase II differentially regulate Axin function in Wnt and JNK pathways
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DOI：
10.1074/jbc.m111982200
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发表时间：
2002-05-17
影响因子：
4.8
通讯作者：
Lin, SC
中科院分区：
文献类型：
--
作者：
Zhang, Y;Qiu, WJ;Lin, SC
Axin在下调Wnt通路和激活MEKK 1/JNK通路中使用不同的功能结构域组合。我们感兴趣的是阐明Axin的功能开关。在本研究中，我们发现Wnt激活剂CKIalpha，而不是CKII alpha，Frat 1，LRP 5或LRP 6，抑制Axin介导的JNK激活。我们还发现，CKIalpha和CKIalpha都与Axin相互作用，而CKII alpha不与Axin结合，对Axin介导的JNK活性没有影响，尽管CKII alpha也被认为是Wnt通路的激活剂。Axin的COOH-末端区域和MEKK 1-相互作用结构域对于CKI α-Axin和CKI ε-Axin相互作用是重要的。我们进一步证明了CKIalpha和CKIalpha与Axin的结合排除了MEKK 1的结合，表明竞争性的物理占用可能是抑制作用的基础。此外，我们的数据表明，CKI激酶活性在这种效应中起着累加作用。总之，我们已经证明，CKI和CKII表现出不同的影响轴MEKK 1相互作用和轴介导的JNK激活。此外，我们的数据表明，CKI可能提供了一个可能的开关机制，Axin功能的调节Wnt和JNK途径。
Axin uses different combinations of functional domains in down-regulation of the Wnt pathway and activation of the MEKK1/JNK pathway. We are interested in the elucidation of the functional switch of Axin. In the present study, we show that the Wnt activator CKIepsilon, but not CKIIalpha, Frat1, LRP5, or LRP6, inhibited Axin-mediated JNK activation. We also found that both CKIalpha and CKIepsilon interacted with Axin, whereas CKIIalpha did not bind to Axin and had no effect on Axin-mediated JNK activity even though CKIIalpha has also been suggested to be an activator for the Wnt pathway. The COOH-terminal region and the MEKK1-interacting domain of Axin are important for CKIalpha-Axin and CKIepsilon-Axin interaction. We further demonstrated that CKIepsilon and CKIalpha binding to Axin excluded MEKK1 binding, indicating that a competitive physical occupancy may underlie the inhibitory effect. Moreover, our data indicated that CKIepsilon kinase activity plays an additive role in this effect. Taken together, we have demonstrated that CKI and CKII exhibit differential effects on Axin-MEKK1 interaction and Axin-mediated JNK activation. Furthermore, our data suggest that CKI may provide a possible switch mechanism for Axin function in the regulation of Wnt and JNK pathways.