Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase
Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase
复制标题
缺氧通过 SIAH2 泛素 E3 连接酶调节 Hippo 信号传导
DOI：
10.1038/ncb3073
复制
发表时间：
2015-01-01
影响因子：
21.3
通讯作者：
Wu, Shian
中科院分区：
文献类型：
--
作者：
Ma, Biao;Chen, Yan;Wu, Shian
Hippo信号通路在动物发育、生理和肿瘤发生中起着重要作用。了解这一途径的活性如何受到细胞微环境的调节仍然是一个重大挑战。在这里，我们阐明了缺氧失活海马信号的分子机制。我们证明，E3泛素连接酶SIAH 2刺激雅普的不稳定LATS 2，海马途径的关键组成部分，在缺氧。SIAH2的缺失在异种移植小鼠模型中以LATS 2依赖性方式抑制肿瘤发生。我们进一步证明了雅普与HIF 1 α复合，并且对于HIF 1 α在体内肿瘤中的稳定性和功能是必需的。LATS 2在人类乳腺肿瘤中下调，并与SIAH2表达水平呈负相关，表明SIAH2-LATS 2通路可能在人类癌症中发挥作用。我们的数据揭示了氧的可用性作为Hippo通路的微环境信号，并对理解肿瘤发生中Hippo信号传导的调节具有意义。
The Hippo signalling pathway plays important roles in animal development, physiology and tumorigenesis,,. Understanding how the activity of this pathway is regulated by the cellular microenvironment remains a major challenge. Here we elucidate a molecular mechanism by which hypoxia deactivates Hippo signalling. We demonstrate that the E3 ubiquitin ligase SIAH2 stimulates YAP by destabilizing LATS2, a critical component of the Hippo pathway, in response to hypoxia. Loss of SIAH2 suppresses tumorigenesis in a LATS2-dependent manner in a xenograft mouse model. We further show that YAP complexes with HIF1α and is essential for HIF1α stability and function in tumoursin vivo. LATS2 is downregulated in human breast tumours and negatively correlates with SIAH2 expression levels, indicating that the SIAH2–LATS2 pathway may have a role in human cancer. Our data uncover oxygen availability as a microenvironment signal for the Hippo pathway and have implications for understanding the regulation of Hippo signalling in tumorigenesis.