Identification of the kinase STK25 as an upstream activator of LATS signaling
Identification of the kinase STK25 as an upstream activator of LATS signaling
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DOI：
10.1038/s41467-019-09597-w
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发表时间：
2019-04-04
影响因子：
16.6
通讯作者：
Ganem, Neil J.
中科院分区：
文献类型：
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作者：
Lim, Sanghee;Hermance, Nicole;Ganem, Neil J.
Hippo通路通过负调节致癌转录共激活因子雅普和TAZ来维持组织稳态。虽然Hippo通路的功能失活在肿瘤中很常见，但核心通路组分的突变很少见。因此，了解肿瘤细胞如何抑制Hippo信号仍然是一个关键的未解决问题。在这里，我们确定激酶STK 25作为Hippo信号传导的激活剂。我们证明，STK 25的损失促进雅普/TAZ激活和增强的细胞增殖，即使在正常的生长抑制条件下，在体外和体内。值得注意的是，STK 25通过促进LATS激活环磷酸化而激活LATS，而不依赖于疏水基序处的先前磷酸化事件，这代表了与LATS的其他激酶激活剂不同的Hippo激活形式。STK 25在广泛的人类癌症中显著局灶性缺失，表明STK 25缺失可能代表肿瘤细胞功能性损害Hippo肿瘤抑制途径的常见机制。
The Hippo pathway maintains tissue homeostasis by negatively regulating the oncogenic transcriptional co-activators YAP and TAZ. Though functional inactivation of the Hippo pathway is common in tumors, mutations in core pathway components are rare. Thus, understanding how tumor cells inactivate Hippo signaling remains a key unresolved question. Here, we identify the kinase STK25 as an activator of Hippo signaling. We demonstrate that loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation, even under normally growth-suppressive conditions both in vitro and in vivo. Notably, STK25 activates LATS by promoting LATS activation loop phosphorylation independent of a preceding phosphorylation event at the hydrophobic motif, which represents a form of Hippo activation distinct from other kinase activators of LATS. STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a common mechanism by which tumor cells functionally impair the Hippo tumor suppressor pathway.