The Laboratory of Cancer Cell Biology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA.
Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, MA, 01605, USA.
Nat Commun. 2019 Apr 4;10(1):1547. doi: 10.1038/s41467-019-09597-w.
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.
Hippo 通路通过负向调控致癌转录共激活因子 YAP 和 TAZ 来维持组织内稳态。尽管 Hippo 通路的功能失活在肿瘤中很常见，但核心通路成分的突变却很少见。因此，了解肿瘤细胞如何使 Hippo 信号失活仍然是一个关键的未解决问题。在这里，我们鉴定出激酶 STK25 是 Hippo 信号的激活剂。我们证明，即使在体外和体内通常的生长抑制条件下，缺失 STK25 也会促进 YAP/TAZ 的激活和增强细胞增殖。值得注意的是，STK25 通过促进 LATS 激活环磷酸化来激活 LATS，而不需要在疏水基序上进行先前的磷酸化事件，这代表了一种不同于其他 LATS 激酶激活剂的 Hippo 激活形式。STK25 在广泛的人类癌症中存在显著的局灶性缺失，这表明 STK25 的缺失可能代表了肿瘤细胞使 Hippo 肿瘤抑制途径功能失调的一种常见机制。
