Choi Jongkyu, Park Sun Young, Costantini Frank, Jho Eek-Hoon, Joo Choun-Ki
Laboratory of Ophthalmology and Visual Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137-701, Korea.
J Biol Chem. 2004 Nov 19;279(47):49188-98. doi: 10.1074/jbc.M404655200. Epub 2004 Sep 7.
Adenomatous polyposis coli (APC) protein and Axin form a complex that mediates the down-regulation of beta-catenin, a key effector of Wnt signaling. Truncation mutations in APC are responsible for familial and sporadic colorectal tumors due to failure in the down-regulation of beta-catenin. While the regulation of beta-catenin by APC has been extensively studied, the regulation of APC itself has received little attention. Here we show that the level of APC is down-regulated by the ubiquitin-proteasome pathway and that Wnt signaling inhibits the process. The domain responsible for the down-regulation and direct ubiquitination was identified. We also show an unexpected role for Axin in facilitating the ubiquitination-proteasome-mediated down-regulation of APC through the oligomerization of Axin. Our results suggest a new mechanism for the regulation of APC by Axin and Wnt signaling.
腺瘤性结肠息肉病蛋白(APC)与Axin形成复合物,介导Wnt信号通路的关键效应分子β-连环蛋白的下调。APC的截短突变由于β-连环蛋白下调失败而导致家族性和散发性结直肠癌。虽然APC对β-连环蛋白的调节已得到广泛研究,但APC自身的调节却很少受到关注。在此我们表明,APC水平通过泛素-蛋白酶体途径下调,且Wnt信号通路抑制该过程。确定了负责下调和直接泛素化的结构域。我们还展示了Axin通过自身寡聚化促进泛素-蛋白酶体介导的APC下调这一出人意料的作用。我们的结果提示了Axin和Wnt信号通路调节APC的新机制。