A gain-of-functional screen identifies the Hippo pathway as a central mediator of receptor tyrosine kinases during tumorigenesis
A gain-of-functional screen identifies the Hippo pathway as a central mediator of receptor tyrosine kinases during tumorigenesis
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DOI：
10.1038/s41388-019-0988-y
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发表时间：
2020-01-01
期刊：
影响因子：
8
通讯作者：
Yang, Xiaolong
中科院分区：
文献类型：
--
作者：
Azad, Taha;Nouri, Kazem;Yang, Xiaolong
Hippo通路已成为调节多种生物功能的关键信号通路。Hippo通路的失调与广泛的人类癌症类型有关。虽然已经报道了一些影响Hippo通路的刺激，但其上游激酶和细胞外调节因子在很大程度上仍然未知。在这里，我们使用RTK过表达文库和Hippo信号活性生物传感器对调节Hippo通路的受体酪氨酸激酶（RTK）进行了首次全面的功能获得筛选。令人惊讶的是，我们发现大多数rtk可以调节Hippo信号活动。我们进一步表征了这些新的关系[TAM家族成员（TYRO3， AXL， METRK）， RET和FGFR家族成员（FGFR1和FGFR2）]，并发现Hippo效应物YAP/TAZ是这些rtk及其细胞外配体（Gas6， GDNF和FGF）通过PI3K或MAPK信号通路诱导的致瘤表型（例如，细胞增殖，转化，细胞运动和血管生成增加）的中心介质。值得注意的是，我们发现FGFR、RET和MERTK是第一批可以直接与YAP/TAZ相互作用并磷酸化多个酪氨酸残基的rtk，而不依赖于上游的Hippo信号，从而激活它们在肿瘤发生中的功能。总之，我们已经确定了几种新的激酶和调节Hippo通路的细胞外刺激。我们的研究结果还强调了Hippo通路在肿瘤发生过程中介导Gas6/GDNF/FGF-TAM/RET/FGFR-MAPK/PI3K信号传导中的关键作用，并为靶向YAP/TAZ治疗rtk驱动的癌症提供了令人信服的理论依据。
The Hippo pathway has emerged as a key signaling pathway that regulates various biological functions. Dysregulation of the Hippo pathway has been implicated in a broad range of human cancer types. While a number of stimuli affecting the Hippo pathway have been reported, its upstream kinase and extracellular regulators remain largely unknown. Here we performed the first comprehensive gain-of-functional screen for receptor tyrosine kinases (RTKs) regulating the Hippo pathway using an RTK overexpression library and a Hippo signaling activity biosensor. Surprisingly, we found that the majority of RTKs could regulate the Hippo signaling activity. We further characterized several of these novel relationships [TAM family members (TYRO3, AXL, METRK), RET, and FGFR family members (FGFR1 and FGFR2)] and found that the Hippo effectors YAP/TAZ are central mediators of the tumorigenic phenotypes (e.g., increased cell proliferation, transformation, increased cell motility, and angiogenesis) induced by these RTKs and their extracellular ligands (Gas6, GDNF, and FGF) through either PI3K or MAPK signaling pathway. Significantly, we identify FGFR, RET, and MERTK as the first RTKs that can directly interact with and phosphorylate YAP/TAZ at multiple tyrosine residues independent of upstream Hippo signaling, thereby activating their functions in tumorigenesis. In conclusion, we have identified several novel kinases and extracellular stimuli regulating the Hippo pathway. Our findings also highlight the pivotal role of the Hippo pathway in mediating Gas6/GDNF/FGF-TAM/RET/FGFR-MAPK/PI3K signaling during tumorigenesis and provide a compelling rationale for targeting YAP/TAZ in RTK-driven cancers.