跨膜蛋白 KIRREL1 通过反馈环调节 Hippo 信号通路，是 YAP/TAZ 活性癌症的治疗靶点。

Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers.

机构信息

Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, the State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032 China.

出版信息

Cell Rep. 2022 Aug 30;40(9):111296. doi: 10.1016/j.celrep.2022.111296.

DOI:10.1016/j.celrep.2022.111296

PMID:36044856

Abstract

The Hippo tumor-suppressor pathway is frequently dysregulated in human cancers and represents a therapeutic target. However, strategies targeting the mammalian Hippo pathway are limited because of the lack of a well-established cell-surface regulator. Here, we show that transmembrane protein KIRREL1, by interacting with both SAV1 and LATS1/2, promotes LATS1/2 activation by MST1/2 (Hippo kinases), and LATS1/2 activation, in turn, inhibits activity of YAP/TAZ oncoproteins. Conversely, YAP/TAZ directly induce the expression of KIRREL1 in a TEAD1-4-dependent manner. Indeed, KIRREL1 expression positively correlates with canonical YAP/TAZ target gene expression in clinical tumor specimens and predicts poor prognosis. Moreover, transgenic expression of KIRREL1 effectively blocks tumorigenesis in a mouse intrahepatic cholangiocarcinoma model, indicating a tumor-suppressor role of KIRREL1. Hence, KIRREL1 constitutes a negative feedback mechanism regulating the Hippo pathway and serves as a cell-surface marker and potential drug target in cancers with YAP/TAZ dependency.

摘要

Hippo 肿瘤抑制途径在人类癌症中经常失调，是一个治疗靶点。然而，由于缺乏成熟的细胞表面调节剂，靶向哺乳动物 Hippo 途径的策略受到限制。在这里，我们发现跨膜蛋白 KIRREL1 与 SAV1 和 LATS1/2 相互作用，促进 MST1/2（Hippo 激酶）对 LATS1/2 的激活，而 LATS1/2 的激活反过来又抑制 YAP/TAZ 癌蛋白的活性。相反，YAP/TAZ 通过 TEAD1-4 依赖性方式直接诱导 KIRREL1 的表达。事实上，KIRREL1 的表达与临床肿瘤标本中典型的 YAP/TAZ 靶基因表达呈正相关，并预示着不良预后。此外，KIRREL1 的转基因表达有效地阻止了小鼠肝内胆管癌模型中的肿瘤发生，表明 KIRREL1 具有肿瘤抑制作用。因此，KIRREL1 构成了调节 Hippo 途径的负反馈机制，并作为具有 YAP/TAZ 依赖性的癌症的细胞表面标志物和潜在药物靶点。