The Drosophila F-box protein Fbxl7 binds to the protocadherin Fat and regulates Dachs localization and Hippo signaling

Abstract

The Drosophila protocadherin Fat (Ft) regulates growth, planar cell polarity (PCP) and proximodistal patterning. A key downstream component of Ft signaling is the atypical myosin Dachs (D). Multiple regions of the intracellular domain of Ft have been implicated in regulating growth and PCP but how Ft regulates D is not known. Mutations in Fbxl7, which encodes an F-box protein, result in tissue overgrowth and abnormalities in proximodistal patterning that phenocopy deleting a specific portion of the intracellular domain (ICD) of Ft that regulates both growth and PCP. Fbxl7 binds to this same portion of the Ft ICD, co-localizes with Ft to the proximal edge of cells and regulates the levels and asymmetry of D at the apical membrane. Fbxl7 can also regulate the trafficking of proteins between the apical membrane and intracellular vesicles. Thus Fbxl7 functions in a subset of pathways downstream of Ft and links Ft to D localization.DOI: http://dx.doi.org/10.7554/eLife.03383.001

Vamana Couples Fat Signaling to the Hippo Pathway

“…Fat also influences growth and Dachs accumulation through a second region of the ICD, the D region (Pan et al, 2013), which interacts with Fbxl7. Because mutation of the D region, or mutations in Fbxl7 (Bosch et al, 2014; Rodrigues-Campos and Thompson, 2014), have weaker phenotypes than mutations in the H region, the H region appears to play the larger role in Dachs regulation, but we nonetheless expect that both regions normally act in parallel to regulate membrane levels of Dachs, and thus ultimately, Hippo signaling.…”

“…One, the D region, around amino acids 4975 to 4993, makes a modest contribution to Hippo pathway regulation, as when this region is deleted flies are viable but their wings are approximately 30% larger than normal (Pan et al, 2013), and also rounder than normal. The D region is required for interaction with the ubiquitin ligase, Fbxl7, which reduces Dachs membrane levels, and mutation of which results in phenotypes similar to deletion of the D region (Bosch et al, 2014; Rodrigues-Campos and Thompson, 2014). A second region, which has been referred to as HM (Bossuyt et al, 2014), Hpo (Matakatsu and Blair, 2012), or H2 (Zhao et al, 2013), is defined by observations that deletions within this region block the ability of Fat to activate Hippo signaling (Fig.…”

“…S1). Two alleles of fat , fat 61 and fat sum , have also been identified that harbor mutations within this region, and are associated with tissue overgrowth comparable to that caused by fat null mutations (Bosch et al, 2014; Bossuyt et al, 2014). However, the mechanism by which this region, which for simplicity we will refer to as the H region, regulates the Hippo pathway, and whether it affects Dachs, are unknown.…”

Local Cell Death Changes the Orientation of Cell Division in the Developing Drosophila Wing Imaginal Disc Without Using Fat or Dachsous as Orienting Signals

“…Effects of Fat and Dachsous on planar cell polarity are mediated by the atypical myosin Dachs and by Atrophin and Fbxl7. The latter two proteins bind to the intracellular domain of Fat [16, 17]. Dachs and Fbxl7 also affect growth, whereas cells lacking Atrophin grow similarly to controls, but lack proper cell division orientation [8, 17–19].…”

Planar Polarity: Converting a Morphogen Gradient into Cellular Polarity

“…Despite its clear effect on Ds–Ft binding, Fj appears to be somewhat redundant with other positive-feedback mechanisms that must help to reinforce small asymmetries and lead to the robustness seen in PCP at the tissue level. One such mechanism may be the amplification of Ft–Ds polarity by the ubiquitin ligase FbxL7, which co-operates with Ft in localizing Ds and the downstream component Dachs to the opposite side of the cell [13,14]. …”