Fig. 5. Cell surface and secreted molecules implicated in Wnt and Hh signaling. (A) In vertebrates, Wnt proteins are inhibited by direct binding to either Frp (Frizzled-related protein), Cerberus (Cer) or Wnt inhibitory factor (Wif). Frp is similar in sequence to the cysteine-rich domain (CRD) of Frizzled, one of the Wnt receptors. The Wnt inhibitors Dickkopf (Dkk) and Wise bind to the Wnt co-receptors Arrow and Lrp (LDL receptor-related protein). Dkk also interacts with Kremen to downregulate these molecules from the surface. Wf/Notum is an extracellular Wingless inhibitor found in Drosophila. In Drosophila, it is also shown that a Wnt can bind to the tyrosine kinase receptor Derailed (RYK in mammals). This receptor has a domain similar to Wif. Heparin-sulfated forms of proteoglycans (HSPG) are also involved in Wnt reception or transport. Boca/Mesd is specifically required for the transport of Arrow/Lrp in the ER. (B) Hh signaling requires the membrane receptors Smoothened (Smo) and Patched and is modulated by HSPGs, which are possibly modified by Tout velu. Megalin, a protein related to Arrow/Lrp has been found to bind to Hh, but only in vertebrates. The Hedgehog inhibitory protein Hip binds to Hh and inhibits its function, but it has only been found in vertebrates. See text for a further explanation of these molecules.