Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.
Sci Rep. 2020 Feb 19;10(1):2957. doi: 10.1038/s41598-020-59899-z.
Wnt/β-catenin signaling is essential for intestinal homeostasis and is aberrantly activated in most colorectal cancers (CRC) through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). APC is an essential component of a cytoplasmic protein complex that targets β-catenin for destruction. Following Wnt ligand presentation, this complex is inhibited. However, a role for APC in this inhibition has not been shown. Here, we utilized Wnt3a-beads to locally activate Wnt co-receptors. In response, the endogenous β-catenin destruction complex reoriented toward the local Wnt cue in CRC cells with full-length APC, but not if APC was truncated or depleted. Non-transformed human colon epithelial cells displayed similar Wnt-induced destruction complex localization which appeared to be dependent on APC and less so on Axin. Our results expand the current model of Wnt/β-catenin signaling such that in response to Wnt, the β-catenin destruction complex: (1) maintains composition and binding to β-catenin, (2) moves toward the plasma membrane, and (3) requires full-length APC for this relocalization.
Wnt/β-catenin 信号通路对于肠道稳态至关重要，并且在大多数结直肠癌（CRC）中通过肿瘤抑制因子腺瘤性结肠息肉病（APC）的突变而异常激活。APC 是一种细胞质蛋白复合物的必需组成部分，该复合物可靶向β-catenin 进行降解。在 Wnt 配体呈现后，该复合物被抑制。然而，APC 在这种抑制中的作用尚未得到证实。在这里，我们利用 Wnt3a-beads 局部激活 Wnt 共受体。作为响应，在全长 APC 的 CRC 细胞中，内源性β-catenin 降解复合物会向局部 Wnt 信号重新定向，但如果 APC 被截断或耗尽则不会。非转化的人结肠上皮细胞显示出类似的 Wnt 诱导的降解复合物定位，这似乎依赖于 APC，而对 Axin 的依赖性较小。我们的结果扩展了目前的 Wnt/β-catenin 信号转导模型，即：（1）维持β-catenin 降解复合物的组成和与β-catenin 的结合；（2）向质膜移动；以及（3）需要全长 APC 进行这种重定位。
