For Wnt Signaling, Fucosylation of LRP6 Is a Bitter Pill

Abstract

In this issue of Cell Chemical Biology, Hong et al. (2020) use in situ chemoenzymatic labeling to discover that fucosylation of the Wnt co-receptor LRP6 induces its endocytosis and downregulates Wnt/b-catenin signaling. Their findings reveal a glycosylation-based mechanism for regulating Wnt signaling that could be targeted in cancer.The promise of molecular medicine relies in large part on our ability to understand and exploit the intricate details of key cellular and physiological signaling pathways that go awry in disease. Among many evolutionarily conserved pathways, Wnt signaling stands out as a major regulator of important cell-fate decisions critical to organogenesis during development, including proliferation, polarization, and migration, as well as tissue homeostasis in adults (MacDonald et al., 2009). Dysregulation of this pathway that pushes its levels outside of the physiological, homeostatic range leads to a variety of devastating diseases, including several cancers (Nusse and Clevers, 2017).The canonical, b-catenin-dependent Wnt signaling pathway initiates at the plasma membrane, where secreted Wnt proteins engage a Frizzled (FZD) receptor along with a key co-receptor, low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), to form a Wnt-FZD-LRP5/6 complex on the surface of the Wntreceiving cell. This binding event induces recruitment of the cytosolic protein Dishevelled (DVL) to the complex on the cytosolic face of plasma membrane, which initiates a cascade that blocks and disassembles a b-catenin destruction complex, resulting in the stabilization and nuclear translocation of b-catenin. Once in nucleus, b-catenin forms an active complex with TCF/LEF transcription factors, leading to expression of several Wnt target genes.

Exogenous l-fucose attenuates neuroinflammation induced by lipopolysaccharide

“…We do not exclude other plausible mechanisms for the l -fucose effects. For instance, α1,3-fucosylation of low-density lipoprotein receptor–related protein 6 could promote its endocytosis, resulting in the inhibition of Wnt–β-catenin signaling, which can be reversed by the exogenous l -fucose ( 91 , 92 ). Detailed information is required for further study.…”