Interactions between the myosin Dachs, the adaptor Dlish, and the palmitoyltransferase Approximated mediate Fat-Dachsous signaling

Bidirectional signaling mediated by heterophilic binding between the giant Drosophila protocadherins Fat and Dachsous (Ds) limits growth through the Hippo pathway and, via patterned binding and cell-by-cell polarization, influences planar cell polarity (PCP) and fate choices along major tissue axes. Prior work showed that the signal transduction initiated by the intracellular domains (ICDs) of Fat and Ds changes the localization and levels of three unusual binding partners: the type XX atypical myosin Dachs, the SH3 domain containing adaptor Dlish, and the DHHC palmitoyltransferase Approximated (App). However, the complex interactions between the three proteins and Fat and Ds are less well understood. Our evidence shows that these proteins play overlapping but distinct roles regulating each other and mediating signaling. Dlish localization and activity requires App binding and palmitoylation. Palmitoylated Dlish helps tether Dachs to the cortex but is also needed to couple Dachs to stabilization by the Ds ICD and destabilization by the Fat ICD. In contrast, Dachs does not localize Dlish but protects it from degradation. Our results also indicate that Fat does not act by changing App levels or localization. We discuss an alternative model based on Dlish's proposed role as an adaptor for E3 ubiquitin ligases.