Hippo 信号传导已成为组织稳态、再生和肿瘤发生的关键调节因子，代表了一个有前途的治疗靶点。神经纤维蛋白 2 (NF2) 是 Hippo 信号传导的一个组成部分，与人类癌症直接相关，但作为癌症治疗的靶点却被忽视。通过高内涵 RNA 干扰全基因组筛选，肌动蛋白结合蛋白 Drebrin (DBN1)已被确定为 YAP 定位的新型调节剂。进一步的研究表明，DBN1 直接与 NF2 相互作用，通过与 LATS 激酶竞争 NF2 结合来破坏大肿瘤抑制激酶 (LATS1/2) 的激活。因此，DBN1敲除显着促进YAP核排斥和靶基因表达抑制，从而防止细胞增殖和肝脏肿瘤发生。我们鉴定了 DBN1-NF2 相互作用所必需的三个赖氨酸残基（K238、K248 和 K252），并开发了一种突变型 DBN1 (DBN1-3Kmut)，该突变型 DBN1 在 NF2 结合方面存在缺陷，并且无法在体外和体外触发 NF2 依赖性 YAP 激活和肿瘤发生。体内。此外，BTP2（一种 DBN1 抑制剂）成功恢复了 NF2-LATS 激酶结合并引发了有效的抗肿瘤活性。索拉非尼和 BTP2 的组合对 HCC 发挥协同抑制作用。我们的研究发现了一种新的 DBN1-NF2-LATS 轴，DBN1 的药理学抑制代表了一种有前途的针对癌症治疗中 Hippo 通路的替代干预措施。版权所有 © 2024 美国癌症协会肝病研究。

The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy.Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, DBN1 knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3Kmut) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC.Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment.Copyright © 2024 American Association for the Study of Liver Diseases.