Endocytosis plays a pivotal regulatory role in canonical WNT signaling. Internalization of the low-density lipoprotein receptor-related protein 6 (LRP6) receptor complex can either promote or attenuate canonical WNT signaling, depending on the employed internalization pathway. Detailed analysis of the mechanism of LRP6 internalization and its temporal regulation is crucial for understanding the different cellular responses to WNT stimulation under varying conditions and in various cell types. Here, we elucidate the mechanisms involved in the internalization of LRP6 and re-evaluate existing, partly contradicting, theories on the regulation of LRP6 receptor internalization. We utilize a computational approach that aims at finding a set of mechanisms that accounts for the temporal dynamics of LRP6 receptor internalization upon WNT stimulation. Starting with a simple simulation model, we successively extend and probe the model's behavior based on quantitative measurements. The final model confirms that LRP6 internalization is clathrin independent in vertebrates, is not restricted to microdomains, and that signalosome formation delays LRP6 internalization within the microdomains. These findings partly revise the current understanding of LRP6 internalization in vertebrates.

内吞作用在经典 WNT 信号传导中发挥着关键的调节作用。低密度脂蛋白受体相关蛋白 6 (LRP6) 受体复合物的内化可以促进或减弱经典 WNT 信号传导，具体取决于所采用的内化途径。详细分析 LRP6 内化机制及其时间调节对于了解不同条件下和不同细胞类型对 WNT 刺激的不同细胞反应至关重要。在这里，我们阐明了 LRP6 内化所涉及的机制，并重新评估了有关 LRP6 受体内化调节的现有的、部分矛盾的理论。我们利用一种计算方法，旨在寻找一组机制来解释 WNT 刺激时 LRP6 受体内化的时间动态。从一个简单的仿真模型开始，我们根据定量测量相继扩展和探索模型的行为。最终模型证实LRP6内化在脊椎动物中不依赖于网格蛋白，不限于微域，并且信号体的形成延迟了微域内的LRP6内化。这些发现部分修正了目前对脊椎动物 LRP6 内化的理解。