Wnt/β-catenin信號通路在發育過程中對細胞生長、細胞分化和細胞存活起關鍵作用。該信號通路失調將導致各種人類疾病，尤其是癌癥。作為Wnt/β-catenin信號通路的一個重要共同受體，低密度脂蛋白受體相關蛋白6(LRP6)的內吞作用和磷酸化在介導Wnt/β-catenin信號傳導中發揮了至關重要的作用。然而，它調控機制仍不完全清楚。

卜國軍教授課題組的研究成果揭示了LRP6的內吞途徑調節其磷酸化和Wnt/β-catenin信號強度的分子機制，這也暗示了在人類疾病中該信號通路是如何受到了調節。該研究成果也開發靶向該信號通路的治療手段的發展也有十分重要的意義。

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.

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