Abstract
Much of the Hippo and planar cell polarity (PCP) signaling mediated by the Drosophila protocadherin Fat depends on its ability to change the subcellular localization, levels and activity of the unconventional myosin Dachs. To better understand this process, we have performed a structure-function analysis of Dachs, and used this to identify a novel and important mediator of Fat and Dachs activities, a Dachs-binding SH3 protein we have named Dlish. We found that Dlish is regulated by Fat and Dachs, that Dlish also binds Fat and the Dachs regulator Approximated, and that Dlish is required for Dachs localization, levels and activity in both wild type and fat mutant tissue. Our evidence supports dual roles for Dlish. Dlish tethers Dachs to the subapical cell cortex, an effect partly mediated by the palmitoyltransferase Approximated under the control of Fat. Conversely, Dlish promotes the Fat-mediated degradation of Dachs.
Highlights
Heterophilic binding between the giant Drosophila protocadherins Fat and Dachsous (Ds) both limits organ growth, via regulation of the Hippo pathway, and orients planar cell polarity (PCP), through cell-by-cell polarization of Fat, Ds and their downstream effectors (Blair, 2012, 2014; Irvine and Harvey, 2015; Matis and Axelrod, 2013)
We show that the activity and subapical concentration of Dlish are regulated by Fat, Discs overgrown (Dco) and Dachs, and that Dlish in turn is required for the subapical concentration and full activity of Dachs in both wild type and fat mutant cells
This rescue requires the presence of adjacent ’PH’ and ’Hippo’ domains in the intracellular domain (ICD) (Matakatsu and Blair, 2012). We extended these studies by testing which domains reduce the increased subapical Dachs of fat mutants
Summary
Heterophilic binding between the giant Drosophila protocadherins Fat and Dachsous (Ds) both limits organ growth, via regulation of the Hippo pathway, and orients planar cell polarity (PCP), through cell-by-cell polarization of Fat, Ds and their downstream effectors (Blair, 2012, 2014; Irvine and Harvey, 2015; Matis and Axelrod, 2013). While players and pathways have been defined that are genetically downstream of Fat-Ds binding, only a little is known about the biochemical links between these and their most powerful regulator, the intracellular domain (ICD) of Fat. A good deal of the recent work on Fat effectors has focused on the regulation of unconventional type XX myosin Dachs (Mao et al, 2006; Matakatsu and Blair, 2008; Rauskolb et al, 2011; Rogulja et al, 2008). Dachs is critical first because it provides the only known marker sensitive to changes in the Fat/Ds branches of both the Hippo and PCP pathways. Downstream changes in Hippo or PCP activities do not affect Dachs
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