功能获得性筛选将 Hippo 通路识别为肿瘤发生过程中受体酪氨酸激酶的中心介质。,Oncogene

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功能获得性筛选将 Hippo 通路识别为肿瘤发生过程中受体酪氨酸激酶的中心介质。
Oncogene ( IF 6.9 ) Pub Date : 2019-09-02 , DOI: 10.1038/s41388-019-0988-y
Taha Azad ₁ , Kazem Nouri ₁ , Helena J Janse van Rensburg ₁ , Sarah M Maritan ₁ , Liqing Wu ₁ , Yawei Hao ₁ , Tess Montminy ₁ , Jihang Yu ₁ , Prem Khanal ₁ , Lois M Mulligan ₁ , Xiaolong Yang ₁

Affiliation

Hippo 通路已成为调节各种生物功能的关键信号通路。Hippo 通路的失调与多种人类癌症类型有关。虽然已经报道了许多影响 Hippo 通路的刺激，但其上游激酶和细胞外调节剂在很大程度上仍然未知。在这里，我们使用 RTK 过表达库和 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) 进行了第一次全面的功能增益筛选。令人惊讶的是，我们发现大多数 RTK 可以调节 Hippo 信号传导活动。我们进一步描述了其中几个新的关系 [TAM 家族成员（TYRO3、AXL、METRK）、RET、和 FGFR 家族成员（FGFR1 和 FGFR2）] 并发现 Hippo 效应子 YAP/TAZ 是这些 RTK 及其细胞外配体诱导的致瘤表型（例如，增加的细胞增殖、转化、增加的细胞运动和血管生成）的中心介质（Gas6、GDNF 和 FGF）通过 PI3K 或 MAPK 信号通路。重要的是，我们将 FGFR、RET 和 MERTK 确定为第一个可以直接与 YAP/TAZ 相互作用并在多个酪氨酸残基处磷酸化 YAP/TAZ，而与上游 Hippo 信号传导无关，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 通路的细胞外刺激物。

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A gain-of-functional screen identifies the Hippo pathway as a central mediator of receptor tyrosine kinases during tumorigenesis.

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.

更新日期：2019-09-03

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