The Hippo in the room: Targeting the Hippo signalling pathway for osteosarcoma therapies.,Journal of Cellular Physiology

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The Hippo in the room: Targeting the Hippo signalling pathway for osteosarcoma therapies.
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2020-07-22 , DOI: 10.1002/jcp.29967
Emel Rothzerg _{1,

2} , Evan Ingley _{3,

4} , Benjamin Mullin _{1,

5} , Wei Xue ₆ , David Wood ₁ , Jiake Xu ₁

Affiliation

Osteosarcoma (OS) is a primary malignant bone tumour which usually occurs in children and adolescents. OS is primarily a result of chromosomal aberrations, a combination of acquired genetic changes and, hereditary, resulting in the dysregulation of cellular functions. The Hippo signalling pathway regulates cell and tissue growth by modulating cell proliferation, differentiation, and migration in developing organs. Mammalian STE20‐like 1/2 (MST1/2) protein kinases are activated by neurofibromatosis type 2, Ras association domain family member 2, kidney and brain protein, or other factors. Interactions between MST1/2 and salvador family WW domain‐containing protein 1 activate large tumour suppressor kinase 1/2 proteins, which in turn phosphorylate the downstream Yes‐associated protein 1/transcriptional coactivator with PDZ‐binding motif (YAP/TAZ). Moreover, dysregulation of this pathway can lead to aberrant cell growth, resulting in tumorigenesis. Interestingly, small molecules targeting the Hippo signalling pathways, through affecting YAP/TAZ cellular localisation and their interaction with members of the TEA/ATTS domain family of transcriptional enhancers are being developed and hold promise for the treatment of OS. This review discusses the existing knowledge about the involvement of the Hippo signalling cascade in OS and highlights several small molecule inhibitors as potential novel therapeutics.

中文翻译：

房间里的河马：针对骨肉瘤治疗的河马信号通路。

骨肉瘤（OS）是一种原发性恶性骨肿瘤，多见于儿童和青少年。OS 主要是染色体畸变、获得性遗传变化和遗传性导致细胞功能失调的组合的结果。Hippo 信号通路通过调节发育器官中的细胞增殖、分化和迁移来调节细胞和组织的生长。哺乳动物 STE20 样 1/2 (MST1/2) 蛋白激酶被 2 型神经纤维瘤病、Ras 关联域家族成员 2、肾和脑蛋白或其他因素激活。MST1/2 和含有萨尔瓦多家族 WW 结构域的蛋白 1 之间的相互作用激活了大型肿瘤抑制激酶 1/2 蛋白，进而磷酸化下游 Yes 相关蛋白 1/具有 PDZ 结合基序 (YAP/TAZ) 的转录共激活因子。此外，该途径的失调可导致异常细胞生长，从而导致肿瘤发生。有趣的是，通过影响 YAP/TAZ 细胞定位及其与转录增强子 TEA/ATTS 域家族成员的相互作用，靶向 Hippo 信号通路的小分子正在开发中，并有望用于治疗 OS。本综述讨论了关于 Hippo 信号级联反应参与 OS 的现有知识，并强调了几种小分子抑制剂作为潜在的新型疗法。通过影响 YAP/TAZ 细胞定位及其与转录增强子 TEA/ATTS 域家族成员的相互作用正在开发中，并有望用于治疗 OS。本综述讨论了关于 Hippo 信号级联反应参与 OS 的现有知识，并强调了几种小分子抑制剂作为潜在的新型疗法。通过影响 YAP/TAZ 细胞定位及其与转录增强子 TEA/ATTS 域家族成员的相互作用正在开发中，并有望用于治疗 OS。本综述讨论了关于 Hippo 信号级联反应参与 OS 的现有知识，并强调了几种小分子抑制剂作为潜在的新型疗法。

更新日期：2020-07-22

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