Desumoylation activity of Axam, a novel Axin-binding protein, is involved in downregulation of β-catenin
Desumoylation activity of Axam, a novel Axin-binding protein, is involved in downregulation of β-catenin
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DOI：
10.1128/mcb.22.11.3803-3819.2002
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发表时间：
2002-06-01
影响因子：
5.3
通讯作者：
Kikuchi, A
中科院分区：
文献类型：
--
作者：
Kadoya, T;Yamamoto, H;Kikuchi, A
Axam是一种新型的Axin结合蛋白，可抑制Wnt信号通路。我们研究了Axam刺激β-连环蛋白下调的分子机制。Axam的C-末端区域具有与SENP 1（SUMO特异性蛋白酶（去小泛素化酶））的催化区域相似的氨基酸序列。实际上，Axam在体外和完整细胞中表现出从小泛素化蛋白中去除SUMO的活性。Axin结合结构域位于Axam的中心区域，不同于催化结构域。无论是Axin结合结构域还是催化结构域单独都不足以下调β-连环蛋白。包含两个结构域的Axam片段能够降低β-连环蛋白的水平。在催化结构域中Ser取代Cys（547）后，Axam失去其去小泛素化活性。此外，这种Axam突变体降低了下调β-连环蛋白的活性。虽然Axam强烈抑制非洲爪蟾胚胎中轴的形成和Wnt反应基因siamois的表达，但Axam（C547S）表现出较弱的活性。这些结果表明Axam作为去小泛素化酶下调β-连环蛋白，并表明小泛素化参与Wnt信号通路的调节。
Axam has been identified as I novel Axin-binding protein that inhibits the Wnt signaling pathway. We studied the molecular mechanism by which Axam stimulates the downregulation of beta-catenin. The C-terminal region of Axam has an amino acid sequence similar to that of the catalytic region of SENP1, a SUMO-specific protease (desumoylation enzyme), Indeed, Axam exhibited activity to remove SUMO from sumoylated proteins in vitro and in intact cells. The Axin-binding domain is located in the central region of Axam, which is different from the catalytic domain. Neither the Axin-binding domain nor the catalytic domain alone was sufficient for the downregulation of beta-catenin. An Axam fragment which contains both domains was able to decrease the level of beta-catenin. On substitution of Ser for Cys(547) in the catalytic domain, Axam lost its desumoylation activity. Further, this Axam mutant decreased the activity to downregulate beta-catenin. Although Axam strongly inhibited axis formation and expression of siamois, a Wnt-response gene, in Xenopus embryos, Axam(C547S) showed weak activities. These results demonstrate that Axam functions as a desumoylation enzyme to downregulate beta-catenin and suggest that sumoylation is involved in the regulation of the Wnt signaling pathway.