Wengen, a Tumour Necrosis Factor Receptor, regulates the Fibroblast Growth Factor pathway by an unconventional mechanism

Unveiling the molecular mechanisms of receptor activation has led to much understanding of development as well as the identification of important drug targets. We use the Drosophila tracheal system to study the activity of two families of widely used and conserved receptors, the TNFRs and the RTK-FGFRs. Breathless, an FGFR, is known to respond to ligand by activating the differentiation program of the tracheal terminal cell. Here we show that Wengen, a TNFR, acts independently of both its canonical ligand and its downstream pathway genes to repress terminal cell differentiation. In contrast to Breathless, Wengen does not stably localise at the membrane and is instead internalised — a trafficking that seems essential for activity. We find that Wengen forms a complex with Breathless, and both colocalise in intracellular vesicles. Furthermore, Wengen regulates Breathless accumulation, likely regulating Breathless intracellular trafficking and degradation. We propose that, in the tracheal context, Wengen interacts with Breathless to regulate its activity in terminal cell differentiation. We suggest that such unconventional mechanism, involving binding by TNFRs to unrelated proteins, may be a general strategy of TNFRs activity.