Focus of chapter

The WNT family consists of 19 lipid-modified secreted glycoproteins with 22 conserved cysteine (Cys) residues (Figure 20.1). WNT proteins are involved in embryogenesis, adult-tissue homeostasis, and carcinogenesis (1–4).

Frizzled family receptors with an extra-cellular Frizzled-like Cys-rich domain (CRD), seven transmembrane domains, and a cytoplasmic Dishevelled-binding motif are representative WNT receptors (5–7). LRP5 and LRP6 with extra-cellular YWTD propeller repeats, epidermal growth factor (EGF) repeats, a single transmembrane domain, and cytoplasmic AXIN-binding PPPSPXS motifs (8,9), as well as ROR1 and ROR2, with an extra-cellular immunoglobulin-like domain, a Frizzled-like CRD, a Kringle domain, a single transmembrane domain, and a cytoplasmic tyrosine kinase domain (10–13) are WNT co-receptors. WNT inhibitory factor (WIF1) and Secreted Frizzled-related protein (SFRP) family members, which directly bind to WNT family members, are secreted-type WNT antagonists (14–17). DKK family members, Sclerostin (SOST), and Wise (SOSTDC1), which bind to WNT co-receptors LRP5 or LRP6, are secreted-type canonical WNT signaling inhibitors (18). Based on the combination of WNT ligands, receptors, and antagonists (Figure 20.2), WNT signals are transduced to canonical and non-canonical signaling cascades in a context-dependent manner (19–21).