Exploring mechanistic and temporal regulation of LRP6 endocytosis in canonical WNT signaling

Abstract

Endocytosis plays a pivotal regulatory role in canonical WNT signaling. Internalization of the LRP6 receptor complex can either promote or attenuate canonical WNT signaling, depending on the employed internalization pathway. A detailed analysis of the mechanism of LRP6 internalization and its temporal regulation is crucial to understand 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 the existing, partly contradicting theories on the regulation of LRP6 receptor internalization. Therefore, 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 and not restricted to microdomains and that the signalosome formation delays the LRP6 internalization within the microdomains. These findings partly revise the current understanding of LRP6 internalization in vertebrates.