Wang J, Ma L, Weng W, Qiao Y, Zhang Y, He J, Wang H, Xiao W, Li L, Chu Q, Pan Q, Yu Y, Sun F

Yes-associated protein (YAP), the downstream effecter of Hippo signaling pathway as well as cAMP response element-binding protein (CREB) has been linked to hepatocarcinogenesis. However, little is known about whether and how YAP and CREB interacts with each other. In this study, we find YAP-CREB interaction is critical for liver cancer ...

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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 closely correlated. Mechanistically CREB promotes YAP transcriptional output through binding to -608/-439, a novel region from 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 leading 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. Conclusion: Our study uncovers a novel positive auto-regulatory feedback loop underlying the interaction between YAP and CREB in liver cancer, suggesting YAP and CREB functions as nexus to integrate the Protein kinase A (PKA), 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. (HEPATOLOGY 2013.).

Date: Mar. 26, 2013

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