Serpentine Proteins Minireview Slither into the Wingless and Hedgehog Fields

extracellular region. These results provide compelling Three recent papers (Bhanot et al., 1996; van den Heuvel evidence that Wg and Dfz2 interact either directly or and Ingham, 1996; Alcedo et al., 1996) report the discovtogether with a co-receptor, as has been observed for ery of putative receptors for both the Wingless (Wg) and other growth factor receptors. Is Dfz2 the Wg receptor Hedgehog (Hh) proteins. These reports are welcome in vivo? Preliminary characterization of the expression news as progress towards an understanding of the regupattern of Dfz2 is consistent with this proposed function. lation of the signaling pathways activated by Wnt and However, the answer to this question will have to await Hh signals has been hampered by the lack of identified the isolation and characterization of Dfz2 mutations. receptors. Wnt and Hh proteins have been implicated Wg is a member of the large family of Wnt secreted in numerous patterning events during development of glycoproteins. To begin addressing the question of both invertebrates and vertebrates. In addition, as is the whether specific Wnts bind to specific Fz proteins, Bhacase for most cell fate determination pathways, abnornot et al. (1996) examined the ability of Wg to bind to mal expression of components of either signaling sysan array of other Fz receptors. They showed that Wg temleads to oncogenesis. In this review, the most recent can bind to some of them, but not all, suggesting that findings and the current working models for these sigWnt and Fz proteins are involved in specific ligand– naling pathways are discussed. receptor interactions. Dfz2, a Candidate Wingless Receptor Downstream of Dfz2 Bhanot et al. (1996) have identified the Drosophila gene, If Fz proteinsencode Wnt receptors, whatare the molecDfz2, as a putative receptor for Wg. Dfz2 encodes a 624 ular events triggered by the activation of these transaminoacid protein that belongs to the Frizzled (Fz) family membrane receptors? Many serpentine receptors are G of serpentine proteins (Vinson et al., 1989; Wang et al., protein–coupled; however, the primary sequences of Fz 1996), which to date includes ten family members from proteins suggest no such connection. Nevertheless, the both vertebrates and invertebrates. Fz proteins possess binding of Wnts to the Fz CRD extracellular domains a putative signal sequence, an extracellular domain could result in a rearrangement of transmembrane docomposed of a conserved region of 120 amino acids mains and activation of downstream cytoplasmic prowith an invariant pattern of ten cysteine residues (the teins (Bhanot et al., 1996). cysteine rich domain, CRD), a highly divergent hyGenetic analysis of Wg signaling in Drosophila has drophylic region of 40–100 amino acids, 7 putative transidentified a number of proteins that have been proposed membrane domains, and a short cytoplasmic domain. to act downstream of the activated Wg receptor (reThe first identified member of this family, frizzled viewed by Perrimon, 1994). In particular, Dsh, a cyto(hereafter referred to as Dfz1; Vinson et al., 1989), was plasmic phosphoprotein absolutely essential for transidentified as a Drosophila gene required for planar polarduction of the Wg signal, is the best candidate for a ity of epithelia. Dfz1 mutations exhibit a “tissue polarity” target of Dfz2. Yanagawa et al. (1995) have proposed phenotype which is visualized by aberrant orientation that, in clone 8 cells, Wg signaling generates a hyperof the single hair secreted by each epidermal cell. A phosphorylated form of Dsh that is membrane associconnection between the Fz and Wnt families of proteins ated. It is unclear whether either of these changes is was indicated by the observation that Dishevelled (Dsh), significant for Dsh signaling function; however, they suga cytoplasmic protein required in receiving cells to transgest a commonly used molecular mechanism whereby duce the Wg signal (Klingensmith et al., 1994), is also activation of a transducing receptor leads to recruitment necessary for Dfz1 signaling (Krasnow et al., 1995). Dfz1 and activation of cytoplasmic molecules. isprobably not a Wg receptor in vivosince Dfz1 mutants, Dsh contains a PDZ domain that could mediate direct unlike wg, do not have a segment polarity phenotype. association with Dfz2. The structure of the third PDZ The discovery of a second Drosophila fz-like gene, Dfz2, domain from the synaptic protein PSD-95 has recently prompted Bhanot and colleagues (1996) to investigate been solved and has revealed that it interacts with a whether Dfz2 and Wg were functionally connected. four residue C-terminal stretch (X-Ser/Thr-X-Val-COO) Previously, van Leeuwen et al. (1994) had developed (Doyle et al., 1996). Because this consensus is present a tissue culture assay for Wg in vitro. In this assay, Wg at the C-terminus of Dfz2, it is possible that activation protein produced and secreted by Drosophila S2 cells of Dfz2 by Wg promotes the recruitment of Dsh to Dfz2. is added in soluble form to the imaginal disc–derived cell This event may lead to Dsh activation, perhaps by a line, clone 8. Clone 8 cells respond to Wg by specifically kinase located at the membrane. Alternatively, the mere increasing the level of hyperphosphorylated Armadillo increase in the level of Dsh at the membrane may lead