Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
Hepatology. 2013 Sep;58(3):1011-20. doi: 10.1002/hep.26420. Epub 2013 Jul 16.
Yes-associated protein (YAP), the downstream effecter of the Hippo-signaling pathway as well as cyclic adenosine monophosphate response element-binding protein (CREB), has been linked to hepatocarcinogenesis. However, little is known about whether and how YAP and CREB interact with each other. In this study, we found that YAP-CREB interaction is critical for liver cancer cell survival and maintenance of transformative phenotypes, both in vitro and in vivo. Moreover, both CREB and YAP proteins are highly expressed in a subset of human liver cancer samples and are closely correlated. Mechanistically, CREB promotes YAP transcriptional output through binding to -608/-439, a novel region from the YAP promoter. By contrast, YAP promotes protein stabilization of CREB through interaction with mitogen-activated protein kinase 14 (MAPK14/p38) and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC). Gain-of-function and loss-of-function studies demonstrated that phosphorylation of CREB by MAPK14/p38 at ser133 ultimately leads to its degradation. Such effects can be enhanced by BTRC through phosphorylation of MAPK14/p38 at Thr180/Tyr182. However, YAP negatively controls phosphorylation of MAPK14/p38 through inhibition of BTRC expression.
There is a novel positive autoregulatory feedback loop underlying the interaction between YAP and CREB in liver cancer, suggesting that YAP and CREB form a nexus to integrate the protein kinase A, Hippo/YAP, and MAPK14/p38 pathways in cancer cells and thus may be helpful in the development of effective diagnosis and treatment strategies against liver cancer.
Yes 相关蛋白（YAP）是 Hippo 信号通路的下游效应物，也是环磷酸腺苷反应元件结合蛋白（CREB），与肝癌发生有关。然而，人们对 YAP 和 CREB 之间是否以及如何相互作用知之甚少。在这项研究中，我们发现 YAP-CREB 相互作用对于肝癌细胞的存活和转化表型的维持至关重要，无论是在体外还是体内。此外，CREB 和 YAP 蛋白在人类肝癌样本的一个亚集中高度表达，并且密切相关。在机制上，CREB 通过与 YAP 启动子上的一个新区域-608/-439 结合来促进 YAP 的转录输出。相比之下，YAP 通过与丝裂原活化蛋白激酶 14（MAPK14/p38）和 β-转导重复序列包含 E3 泛素蛋白连接酶（BTRC）相互作用来促进 CREB 蛋白的稳定。功能获得和功能丧失研究表明，MAPK14/p38 在丝氨酸 133 处对 CREB 的磷酸化最终导致其降解。这种效应可以通过 BTRC 在 Thr180/Tyr182 处对 MAPK14/p38 的磷酸化来增强。然而，YAP 通过抑制 BTRC 表达负调控 MAPK14/p38 的磷酸化。
肝癌中 YAP 和 CREB 相互作用的基础是一个新的正反馈回路，这表明 YAP 和 CREB 形成了一个枢纽，整合了蛋白激酶 A、Hippo/YAP 和 MAPK14/p38 通路在癌细胞中，因此可能有助于开发针对肝癌的有效诊断和治疗策略。
