Cell competition is a conserved homeostatic mechanism whereby epithelial cells eliminate neighbors with lower fitness. Cell communication at the interface of wild-type “winner” cells and polarity-deficient (scrib^−/−) “losers” is established through Sas-mediated Ptp10D activation in polarity-deficient cells. This tumor-suppressive cell competition restrains EGFR and Hippo signaling and enables Eiger-JNK mediated apoptosis in scrib^−/− clones. Here, we show that the activation state of the endosomal actin regulator WASH is a central node linking EGFR and Hippo signaling activation. The tyrosine kinase Btk29A and its substrate WASH are required downstream of Ptp10D for “loser” cell elimination. Constitutively active, phosphomimetic WASH is sufficient to induce both EGFR and Yki activation leading to overgrowth. On the mechanistic level we show that Ptp10D is recycled by the WASH/retromer complex, while EGFR is recycled by the WASH/retriever complex. Constitutive WASH activation selectively interferes with retromer function leading to Ptp10D mistargeting while promoting EGFR recycling and signaling activation. Phospho-WASH also activates aberrant Arp2/3 actin polymerization, leading to cytoskeletal imbalance, Yki activation and reduced apoptosis. Selective manipulation of WASH phosphorylation on sorting endosomes may restrict epithelial tumorous growth.

细胞竞争是一种保守的稳态机制，上皮细胞通过这种机制消除适应性较低的邻居。野生型“赢家”细胞和极性缺陷型 ( scrib ^-/- )“输家”的界面处的细胞通讯是通过极性缺陷细胞中 Sas 介导的 Ptp10D 激活建立的。这种肿瘤抑制细胞竞争抑制 EGFR 和 Hippo 信号，并使 Eiger-JNK 介导的scrib细胞凋亡^-/-克隆人。在这里，我们表明内体肌动蛋白调节剂 WASH 的激活状态是连接 EGFR 和 Hippo 信号激活的中心节点。酪氨酸激酶 Btk29A 及其底物 WASH 是 Ptp10D 下游用于消除“失败者”细胞所必需的。具有组成型活性的拟磷酸化 WASH 足以诱导 EGFR 和 Yki 激活，从而导致过度生长。在机制层面上，我们表明 Ptp10D 由 WASH/retromer 复合体回收，而 EGFR 由 WASH/retriever 复合体回收。本构 WASH 激活选择性地干扰逆转录酶功能，导致 Ptp10D 错误定位，同时促进 EGFR 循环和信号激活。Phospho-WASH 还激活异常的 Arp2/3 肌动蛋白聚合，导致细胞骨架失衡、Yki 激活和细胞凋亡减少。