ESCRT-0 complex modulates Rbf mutant cell survival by regulating Rhomboid endosomal trafficking and EGFR signaling

The Rb tumor suppressor is conserved in Drosophila and its inactivation can lead to cell proliferation or death depending on the specific cellular context. Therefore identifying genes that affect the survival of Rb mutant cells can potentially identify novel targets for cancer therapeutic intervention. From a genetic screen in Drosophila, we identified synthetic lethal interactions between mutations of fly Rb (rbf) and the ESCRT-0 components, stam and hrs. We show that inactivation of ESCRT-0 sensitizes rbf-mutant cells to apoptosis by inhibition of EGFR signaling and accumulation of Hid protein. Mutation of stam inhibits EGFR signaling upstream of secreted Spi and downstream of Rhomboid expression and causes Rhomboid protein to accumulate in the abnormal endosomes labelled with both the early and late endosomal markers Rab5 and Rab7. These results reveal that ESCRT-0 mutants inhibit EGFR signaling by disrupting Rhomboid endosomal trafficking in the ligand producing cells. Since ESCRT-0 also plays critical roles in EGFR downregulation after ligand binding, this study provides new insights into how loss of ESCRT-0 function can either increase or decrease EGFR signaling.