LRPs in WNT Signalling

Abstract

The WNT/β-catenin signalling pathway is a rich and complex network of cellular proteins that orchestrates diverse short-range cell-to-cell communication in metazoans and is essential for both embryonic development and adult homeostasis. Due to its fundamental importance in controlling cell behaviour at multiple levels, its deregulation is associated with a wide range of diseases in humans and identification of drugs targeting the pathway has attracted strong interest in the pharmaceutical sector. Transduction of WNT signals across the plasma membrane of cells involves a staggering degree of complexity and variety with respect to ligand-receptor, receptor-receptor and receptor-co-receptor interactions (Niehrs, Nat Rev Mol Cell Biol 13:767-779, 2012). Although the low-density-lipoprotein-receptor-related-protein (LRP) family is best known for its role in binding and endocytosis of lipoproteins, specific members appear to have additional roles in cellular communication. Indeed, for WNT/β-catenin signalling one apparently universal requirement is the presence of either LRP5 or LRP6 in combination with one of the ten Frizzled (FZD) WNT receptors (FZD_1-10). In the 20 years since their discovery as WNT/FZD co-receptors, research on the LRP family has contributed greatly to our understanding of WNT signalling and LRPs have emerged as central players in WNT/β-catenin signalling. LRP5/6 are highly similar and represent the least redundant class of WNT receptor that transduce WNT/β-catenin signalling from a wide range of different WNT and FZD subtypes. This apparent simplicity however belies the complex arrangement of binding sites in the extracellular domain (ECD) of LRP5/6, which regulate interaction not only with WNTs but also with several inhibitors of WNT signalling. This chapter provides a historical overview, chronologically charting this remarkable progress in the field during the last 20 years of research on LRPs and their role in WNT/-catenin signalling. A more focused overview of the structural, functional and mechanistic aspects of LRP biology is also provided, together with the implications this has for pharmacological targeting of this notoriously intractable pathway.

Keywords: DKK therapeutic antibodies; LRP; LRP4; LRP5; LRP5 disease mutations; LRP6; LRP6 disease mutations; LRP6 structure; Sclerostin therapeutic antibodies; Wnt; Wnt co-receptor; Wnt surrogates.