Actin cytoskeletal deregulation, caused by RhoGEF2 overexpression, induces cell competition dependent on Ptp10D, Crumbs, and the Hippo signaling pathway

InDrosophilalarval epithelial tissues, cells containing mutations in the apico-basal polarity proteins, Scrib, Dlg or Lgl, are eliminated by cell competition when surrounded bywild-typecells. In these polarity-impaired cells, signaling mediated by the receptor-type tyrosine phosphatase Ptp10D upon engagement with its ligand Sas in the surroundingwild-typecells triggers cell competition via EGFR pathway inhibition and JNK pathway activation, which induces apoptosis of the mutant cells. Here, we investigate whether directly triggering cytoskeletal deregulation (which usually occurs downstream of cell polarity disruptions) is sufficient to trigger their elimination by cell competition via the Sas-Ptp10D signaling system. We show that actin cytoskeleton deregulated cells (as induced byRhoGEF2overexpression (RhoGEF2^OE)) are eliminated when surrounded bywild-typecells, and thatPtp10Dknockdown increasesRhoGEF2^OEclone growth, revealing the importance of Ptp10D in the elimination ofRhoGEF2^OEcells. Mechanistically, in clones that are moderately overexpressingRhoGEF2^OE, Ptp10Dknockdown rescued cell elimination by reducing Hippo signaling. In this setting, JNK and EGFR-Ras signaling were not affected (in contrast to what occurs in apico-basal mutant cells), suggesting that Sas-Ptp10D may regulate the Hippo pathway directly inRhoGEF2^OEcells. We also found that mutations in the apical cell polarity protein, Crb, partially rescued the elimination ofRhoGEF2^OEclones, showing that Crb normally plays a role inRhoGEF2^OEclone elimination. In this setting, in whichRhoGEF2^OEis highly overexpressed, JNK and Hippo signaling were elevated while EGFR-Ras signaling was reduced, andcrbloss normalized these pathways.crbmutant cells also showed reduced abundance of and apical membrane localization of Ptp10D, suggesting that Crb may play an important role in Sas-Ptp10D mediated cell competition. Thus, actin cytoskeleton deregulation, caused byRhoGEF2^OE, results in clone elimination dependent on Crb, Ptp10D, and Hippo signaling. Altogether, our results reveal that Ptp10D is acting more broadly in cell competition to trigger the elimination of actin cytoskeleton deregulated loser cells, as well as polarity-impaired cells.