YAP 及其旁系同源物 TAZ/WWTR1 的相反表达和促癌或抗癌功能将癌症分为二元 YAPon 和 YAPoff 类别。这些转录共激活因子在 YAPon 癌症中具有致癌性。相比之下，在神经和神经内分泌 YAPoff 癌症（例如小细胞肺癌、视网膜母细胞瘤）中，YAP/TAZ 及其整合素和细胞外基质粘附靶基因在表观遗传学上被沉默。强制 YAP/TAZ 表达诱导这些靶标，部分通过整合素-αV/β5 引起细胞抑制，独立于整合素结合 RGD 配体。 YAP 抗癌功能的其他效应器尚不清楚。在这里，我们使用 CRISPR 筛选，将 Netrin 受体 UNC5B 与 YAPoff 癌症中 YAP 诱导的细胞抑制联系起来。强制 YAP 表达通过 TEAD DNA 结合伴侣诱导 UNC5B，因为 TEAD1/4 缺失或 YAP 突变会破坏 TEAD 结合 (S94A) 阻断，而 TEAD 激活剂融合 (TEAD(DBD)-VP64) 则促进 UNC5B 诱导。在 YAPoff 癌症中，异位 YAP 表达还会上调 UNC5B 相关蛋白及其 netrin 配体。 Netrins 被认为是促肿瘤发生的，但敲除和肽/诱饵受体阻断测定表明，在 YAPoff 癌症中，UNC5B 和 Netrin-1 可以与整合素-αV/β5 配合介导 YAP 诱导的细胞抑制。这些数据明确指出 Netrin-1/UNC5B/整合素-αV/β5 轴是 YAP 肿瘤抑制活性的关键效应子。

Opposite expression and pro- or anti-cancer function of YAP and its paralog TAZ/WWTR1 stratify cancers into binary YAPon and YAPoff classes. These transcriptional coactivators are oncogenic in YAPon cancers. In contrast, YAP/TAZ are silenced epigenetically along with their integrin and extracellular matrix adhesion target genes in neural and neuroendocrine YAPoff cancers (e.g., small cell lung cancer, retinoblastoma). Forced YAP/TAZ expression induces these targets, causing cytostasis in part through Integrin-αV/β5, independent of the integrin-binding RGD ligand. Other effectors of this anti-cancer YAP function are unknown. Here, using CRISPR screens, we link the Netrin receptor UNC5B to YAP-induced cytostasis in YAPoff cancers. Forced YAP expression induces UNC5B through TEAD DNA-binding partners, as either TEAD1/4-loss or a YAP mutation that disrupts TEAD-binding (S94A) blocks whereas a TEAD-activator fusion (TEAD(DBD)-VP64) promotes UNC5B induction. Ectopic YAP expression also upregulates UNC5B relatives and their netrin ligands in YAPoff cancers. Netrins are considered pro-tumorigenic, but knockout and peptide/decoy-receptor blocking assays reveal that in YAPoff cancers UNC5B and Netrin-1 can cooperate with integrin-αV/β5 to mediate YAP-induced cytostasis. These data pinpoint an unsuspected Netrin-1/UNC5B/integrin-αV/β5 axis as a critical effector of YAP tumor suppressor activity.