title: Mutual interaction between YAP and CREB promotes tumorigenesis in liver cancer.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wang
authors.forename: Lifang
authors.initials: L
authors.lastname: Ma
authors.forename: Wenhao
authors.initials: W
authors.lastname: Weng
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Qiao
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jiangtu
authors.initials: J
authors.lastname: He
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.forename: Weifan
authors.initials: W
authors.lastname: Xiao
authors.forename: Lanlan
authors.initials: L
authors.lastname: Li
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Chu
authors.forename: Qiuhui
authors.initials: Q
authors.lastname: Pan
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Yu
authors.forename: Fenyong
authors.initials: F
authors.lastname: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D064593:Heterografts; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C471644:BTRC protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D044844:beta-Transducin Repeat-Containing Proteins; D048308:Mitogen-Activated Protein Kinase 14; D048051:p38 Mitogen-Activated Protein Kinases