Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, 200072 Shanghai, China.
Department of Clinical Laboratory Medicine, Tong Ren Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 200336 Shanghai, China.
FEBS Lett. 2014 Nov 28;588(23):4334-41. doi: 10.1016/j.febslet.2014.09.042. Epub 2014 Oct 13.
Tribbles homolog 2 (TRIB2) is specifically regulated by Wnt signaling in liver cancer cells but not in colon cancer cells. However, whether and how TRIB2 regulates Wnt signaling in liver cancer cells remains unclear. Here, we report that TRIB2 negatively regulates Wnt activity through a reduction in protein stability of TCF4 and β-Catenin. Mechanistically, TRIB2 associated-ubiquitin E3 ligases beta-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP), COP1 and Smad ubiquitination regulatory factor 1 (Smurf1) reduced TCF4/β-Catenin expression, and these effects could be enhanced by TRIB2. Moreover, deletion of the binding regions of these E3-ligases within the TRIB2 protein decreased ubiquitination of TCF4/β-Catenin and reduced nuclear accumulation of β-TrCP, COP1 and Smurf1, which suggested that TRIB2 regulated-Wnt activity is closely correlated with its associated E3 ligases.
原癌基因 Tribbles 同源物 2（TRIB2）在肝癌细胞中受 Wnt 信号通路的特异性调控，但在结肠癌细胞中不受调控。然而，TRIB2 是否以及如何在肝癌细胞中调节 Wnt 信号通路尚不清楚。在这里，我们报告称，TRIB2 通过降低 TCF4 和 β-Catenin 的蛋白稳定性来负调控 Wnt 活性。在机制上，TRIB2 相关的泛素 E3 连接酶 β-转导重复蛋白 E3 泛素蛋白连接酶（β-TrCP）、COP1 和 Smad 泛素化调节因子 1（Smurf1）降低了 TCF4/β-Catenin 的表达，并且这些作用可以被 TRIB2 增强。此外，TRIB2 蛋白内这些 E3 连接酶的结合区域缺失可减少 TCF4/β-Catenin 的泛素化，并减少 β-TrCP、COP1 和 Smurf1 的核内积累，这表明 TRIB2 调节的 Wnt 活性与其相关的 E3 连接酶密切相关。
