Wnt/β-catenin信号通路在发育过程中对细胞生长、细胞分化和细胞存活起关键作用。该信号通路失调将导致各种人类疾病，尤其是癌症。作为Wnt/β-catenin信号通路的一个重要共同受体，低密度脂蛋白受体相关蛋白6(LRP6)的内吞作用和磷酸化在介导Wnt/β-catenin信号传导中发挥了至关重要的作用。然而，它调控机制仍不完全清楚。

卜国军教授课题组的研究成果揭示了LRP6的内吞途径调节其磷酸化和Wnt/β-catenin信号强度的分子机制，这也暗示了在人类疾病中该信号通路是如何受到了调节。该研究成果也开发靶向该信号通路的治疗手段的发展也有十分重要的意义。

原文摘要：

Tyrosine-based Signal Mediates LRP6 Endocytosis and Desensitization of Wnt/β-catenin Signaling

Chia-Chen Liu, Kanekiyo Takahisa, Barbara Roth and Guojun Bu

Wnt/β-catenin signaling orchestrates a number of critical events including cell growth, differentiation and cell survival during development. Misregulation of this pathway leads to various human diseases, specifically cancers. Endocytosis and phosphorylation of the LDL receptor-related protein 6 (LRP6), an essential co-receptor for Wnt/β-catenin signaling, play a vital role in mediating Wnt/β-catenin signal transduction. However, its regulatory mechanism is not fully understood. In this study, we define the mechanisms by which LRP6 endocytic trafficking regulates Wnt/β-catenin signaling activation. We show that LRP6 mutant with defective tyrosine-based signal in its cytoplasmic tail has an increased cell surface distribution and decreased endocytosis rate. These changes in LRP6 endocytosis coincide with an increased distribution to caveolae, increased phosphorylation, and enhanced Wnt/β-catenin signaling. We further demonstrate that treatment of Wnt3a ligands or blocking the clathrin-mediated endocytosis of LRP6 lead to a redistribution of wild-type receptor to lipid rafts. The LRP6 tyrosine mutant also exhibited an increase in signaling activation in response to Wnt3a stimulation compared to wild-type LRP6, and this activation is suppressed when caveolae-mediated endocytosis is blocked. Our results reveal molecular mechanisms by which LRP6 endocytosis routes regulate its phosphorylation and the strength of Wnt/β-catenin signaling, and have implications on how this pathway can be modulated in human diseases.

购买进口仪器、试剂和耗材——就在始于2001年的毕特博生物 www.bitebo.com