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First published online October 6, 2003
doi: 10.1242/10.1242/dev.00821

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Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface

Howard Hughes Medical Institute, Department of Developmental Biology, Beckman Center, Stanford University, Stanford, CA 94305, USA

View larger version (23K): [in a new window]   Fig. 1. Production of lipid-modified Wnt and Hedgehog (Hh) proteins. (A) Porcupine (Porc), or MOM-1 in C. elegans, is an endoplasmic reticulum (ER) protein that is required in Wnt producing cells, and which is thought to attach a palmitate to Wnt. In C. elegans, the MOM-3 gene product (not yet identified molecularly) may assist in the production or release of active Wnt. (B) In Hh-producing cells, Rasp is necessary for the acylation of the Hh protein. The C terminus of Hh is cholesterol-modified. Release of lipid-modified Hh requires the transmembrane protein Dispatched (Disp). (C,D) The Wnt (C) and Hh (D) proteins, showing the approximate positions of cysteine residues (blue vertical lines) and lipid modifications.

View larger version (13K): [in a new window]   Fig. 2. Positions of palmitoylated cysteines in Hh and Wnt. Palmitoylated cysteines (C) are shown in bold. In Hh, this cysteine is at the N terminus after the signal sequence (underlined) has been removed (Pepinsky et al., 1998). The cysteine in the Wnt protein Wnt3A and, by homology, in Wingless (Wg; shown here), is internal. However, this does not exclude the possibility that Wnt carries additional modifications at other sites. In both Hh and Wnt, there are basic residues downstream of the modified cysteine (shown in red).

View larger version (20K): [in a new window]   Fig. 4. Wnt and Hedgehog (Hh) acylation and the role of Porc and Rasp. (A) The palmitoylation of wild-type Wnt and Hh proteins. Wnt is palmitoylated through a thioesther to a cysteine. Dashed lines indicate the possibility of disulphide formation between other cysteines in Wnts. Hh is palmitoylated through an amide on the N-terminal cysteine. The two other cysteines in Hh are not disulphide linked and have free sulfhydryl (SH) groups. (B) In the absence of Porc, Wnt is not palmitoylated on the first cysteine. This cysteine then has a free SH group that interferes with disulphide formation between other cysteines. The resulting protein is midfolded and will not be secreted. In the absence of Rasp, the first cysteine in Hh is not palmitoylated but the number of free SH groups does not change and the Hh protein is still secreted.

View larger version (81K): [in a new window]   Fig. 3. Staining for the Wingless (Wg) protein in Drosophila tissues. (A) In wild-type (wt) embryos, Wg staining (green) is diffuse, indicating that the protein is secreted. (B) In embryos carrying the wgS21 allele, Wg appears to be confined to cells and not secreted. (C) In a porcupine (porc)-mutant embryo, Wg is also confined to producing cells, indicating that it is not secreted. (D,E) Staining for the Wg protein (green) in a wing imaginal disc that contains a clone of cells mutant for porc. The position of the clone is indicated by a lack of staining for ß-galactosidase (red) and is outlined (D). The clone contains cells of the dorsal-ventral wing boundary where Wg is made. In the clone, Wg protein accumulates and is not secreted (arrows). Data provided by Wendy Ching (see also van den Heuvel et al., 1993).

View larger version (31K): [in a new window]   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.