Wnt/β-catenin信號通路在發(fā)育過程中對細(xì)胞生長、細(xì)胞分化和細(xì)胞存活起關(guān)鍵作用。該信號通路失調(diào)將導(dǎo)致各種人類疾病，尤其是癌癥。作為Wnt/β-catenin信號通路的一個(gè)重要共同受體，低密度脂蛋白受體相關(guān)蛋白6(LRP6)的內(nèi)吞作用和磷酸化在介導(dǎo)Wnt/β-catenin信號傳導(dǎo)中發(fā)揮了至關(guān)重要的作用。然而，它調(diào)控機(jī)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(nèi)吞途徑調(diào)節(jié)其磷酸化和Wnt/β-catenin信號強(qiáng)度的分子機(jī)制，這也暗示了在人類疾病中該信號通路是如何受到了調(diào)節(jié)。該研究成果也開發(fā)靶向該信號通路的治療手段的發(fā)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.

購買進(jìn)口儀器、試劑和耗材——就在始于2001年的畢特博生物 www.gducity.com