Hippo 信号通路在人类癌症中通常失调，这导致肿瘤对 YAP/TAZ 转录共激活因子的强烈依赖。在这里，我们使用旁系同源共靶向 CRISPR 筛选来鉴定激酶 MARK2/3 作为不同癌症和肉瘤中 YAP/TAZ 功能的绝对催化要求。这一观察结果的基础是 NF2 和 YAP/TAZ 的直接 MARK2/3 依赖性磷酸化，它有效逆转 Hippo 模块激酶 LATS1/2 的肿瘤抑制活性。为了模拟 MARK2/3 的靶向，我们将来自幽门螺杆菌的 CagA 蛋白改造为 MARK2/3 的催化抑制剂，我们证明它可以消退体内已形成的肿瘤。总之，这些发现揭示了 MARK2/3 在人类癌症中与 YAP/TAZ 具有强大的相互依赖性；可能允许恢复 Hippo 通路介导的肿瘤抑制的药理学目标。

The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.