Proteolytic processing of LRP6 and its effects on canonical Wnt signaling

Abstract

LRP6 acts as a co-receptor in the canonical Wnt pathway, a key signaling network involved in regulating embryonic development, tissue patterning, cell migration, and homeostasis. Aberrations in the canonical Wnt pathway are often correlated with various types of cancers. Mutants of the LRP6 co-receptor lacking the majority of the extracellular domain are able to constitutively activate the Wnt pathway. Recently, it was discovered that LRP6 undergoes regulated intramembrane proteolysis (RIP). RIP is a two-step process wherein transmembrane proteins are cleaved first in the extracellular region releasing a soluble form of the extracellular domain, followed by cleavage in the transmembrane region that releases a biologically active intracellular domain (ICD). How LRP6 undergoes RIP and its potential implications for the regulation of the canonical Wnt pathway remain unclear. The goal of this thesis was to elucidate the mechanism and conditions in which LRP6 is cleaved and confirm the responsible proteases. The project also analyzed the effects of a novel mutation that renders the co-receptor resistant to cleavage. Together, the data revealed a complex process by which LRP6 is subjected to RIP possibly through the recruitment of ADAM10 by EphrinB2 and subsequent intramembrane cleavage by y-secretase. Additionally, this mechanism may only occur in cellular environments where Wnt ligand concentrations are sufficiently low enough to cause an alternative route of Wnt activation.