The Hippo pathway effector Yes-associated protein (YAP) is localized to the nucleus and transcriptionally active in a number of tumor types, including a majority of human cholangiocarcinomas. YAP activity has been linked to chemotherapy resistance and has been shown to rescue KRAS and BRAF inhibition in RAS/RAF-driven cancers; however, the underlying mechanisms of YAP-mediated chemoresistance have yet to be elucidated. Herein, we report that the tyrosine phosphatase SHP2 directly regulates the activity of YAP by dephosphorylating pYAPY357 even in the setting of RAS/RAF mutations, and that diminished SHP2 phosphatase activity is associated with chemoresistance in cholangiocarcinomas. A screen for YAP-interacting tyrosine phosphatases identified SHP2, and characterization of cholangiocarcinomas cell lines demonstrated an inverse relationship between SHP2 levels and pYAPY357. Human sequencing data demonstrated lower SHP2 levels in cholangiocarcinomas tumors as compared with normal liver. Cell lines with low SHP2 expression and higher levels of pYAPY357 were resistant to gemcitabine and cisplatin. In cholangiocarcinomas cells with high levels of SHP2, pharmacologic inhibition or genetic deletion of SHP2 increased YAPY357 phosphorylation and expression of YAP target genes, including the antiapoptotic regulator MCL1, imparting resistance to gemcitabine and cisplatin. In vivo evaluation of chemotherapy sensitivity demonstrated significant resistance in xenografts with genetic deletion of SHP2, which could be overcome by utilizing an MCL1 inhibitor. Implications: These findings demonstrate a role for SHP2 in regulating YAP activity and chemosensitivity, and suggest that decreased phosphatase activity may be a mechanism of chemoresistance in cholangiocarcinoma via a MCL1-mediated mechanism.

中文翻译：

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YAP 相互作用磷酸酶 SHP2 可以调节转录共活性并调节胆管癌对化疗的敏感性

Hippo 通路效应子 Yes 相关蛋白 (YAP) 定位于细胞核，在多种肿瘤类型中具有转录活性，包括大多数人类胆管癌。YAP 活性与化疗耐药有关，并已被证明可以挽救 RAS/RAF 驱动的癌症中的 KRAS 和 BRAF 抑制；然而，YAP 介导的化学抗性的潜在机制尚未阐明。在此，我们报告即使在 RAS/RAF 突变的情况下，酪氨酸磷酸酶 SHP2 也通过使 pYAPY357 去磷酸化直接调节 YAP 的活性，并且 SHP2 磷酸酶活性的降低与胆管癌的化学抗性有关。YAP 相互作用酪氨酸磷酸酶的筛选鉴定了 SHP2，胆管癌细胞系的研究和表征表明 SHP2 水平与 pYAPY357 呈负相关。人类测序数据表明，与正常肝脏相比，胆管癌肿瘤中的 SHP2 水平较低。具有低 SHP2 表达和较高水平 pYAPY357 的细胞系对吉西他滨和顺铂具有抗性。在具有高水平 SHP2 的胆管癌细胞中，SHP2 的药理抑制或基因缺失增加了 YAPY357 磷酸化和 YAP 靶基因（包括抗凋亡调节剂 MCL1）的表达，从而赋予对吉西他滨和顺铂的抗性。化疗敏感性的体内评估表明，在 SHP2 基因缺失的异种移植物中存在显着的耐药性，这可以通过使用 MCL1 抑制剂来克服。含义：