title: A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.
abstract: YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation.
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Toshiro
authors.initials: T
authors.lastname: Moroishi
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA; Department of Laboratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China;
authors.forename: Baodong
authors.initials: B
authors.lastname: Qin
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Steven W
authors.initials: SW
authors.lastname: Plouffe
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA; Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Children's Hospital, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Fa-Xing
authors.initials: FX
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA; Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002465:Cell Movement; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D025581:Neurofibromin 2 / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025581:Neurofibromin 2; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse; C490501:Lats1 protein, mouse; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; TAZ; YAP; cancer; negative feedback; phosphorylation