Endocytosis and signaling in the Drosophila wingless (Wnt -1) pathway

During animal development, the conserved Wnt signaling pathway is required for the patterning of multiple tissues. Writs are important mediators of cell-cell communication, therefore the duration of the Wnt signal must be confined both temporally and spatially to ensure the appropriate developmental response. In Drosophila, the Wnt-1 homologue Wingless (Wg) signals through two cell surface receptors, DFrizzled-2 (DFz2) and co-receptor Arrow. Here we present evidence that the Wg-induced physical proximity of DFz2 and Arrow triggers pathway activation. The receptor complex recruits the negative regulator Axin to the plasma membrane via the interaction of Axin with the C-terminus of Arrow. This translocation sequesters Axin from the Armadillo (Arm) destruction complex, leading to accumulation of Arm and signal transduction. In addition to their role in initiating the Wg signal, Arrow and DFz2 contain putative endocytic motifs, suggesting that they may be important for the endocytic trafficking of Wg. Endocytic trafficking has recently been proposed as an important mechanism to regulate signal transduction. We characterize the vesicular trafficking of Wg and its receptors, and investigate whether trafficking is important to regulate Wg signaling during dorsoventral patterning of the larval wing. We show that Arrow and DFz2 function as endocytic receptors for Wg. Following internalization from the membrane, Wg, Arrow and DFz2 are trafficked through the endocytic pathway to the lysosome, where they are degraded in a Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-dependent manner. Surprisingly, we find that Wg signaling is not attenuated by lysosomal targeting in the wing disc. Rather, we suggest that signaling is dampened intracellularly at an earlier trafficking step. This is in contrast to patterning of the embryonic epidermis, where lysosomal targeting is required to restrict the range of Wg signaling. Thus, signal modulation by endocytic routing will depend on the tissue to be patterned and the goals during that patterning event