title: TAZ Protein Accumulation Is Negatively Regulated by YAP Abundance in Mammalian Cells.
abstract: The mammalian Hippo signaling pathway regulates cell growth and survival and is frequently dysregulated in cancer. YAP and TAZ are transcriptional coactivators that function as effectors of this signaling pathway. Aberrant YAP and TAZ activity is reported in several human cancers, and normally the expression and nuclear localization of these proteins is tightly regulated. We sought to establish whether a direct relationship exists between YAP and TAZ. Using knockdown and overexpression experiments we show YAP inversely regulates the abundance of TAZ protein by proteasomal degradation. Interestingly this phenomenon was uni-directional since TAZ expression did not affect YAP abundance. Structure/function analyses suggest that YAP-induced TAZ degradation is a consequence of YAP-targeted gene transcription involving TEAD factors. Subsequent investigation of known regulators of TAZ degradation using specific inhibitors revealed a role for heat shock protein 90 and glycogen synthase kinase 3 but not casein kinase 1 nor LATS in YAP-mediated TAZ loss. Importantly, this phenomenon is conserved from mouse to human; however, interestingly, different YAP isoforms varied in their ability to degrade TAZ. Since shRNA-mediated TAZ depletion in HeLa and D645 cells caused apoptotic cell death, we propose that isoform-specific YAP-mediated TAZ degradation may contribute to the contradicting roles reported for YAP overexpression. This study identifies a novel mechanism of TAZ regulation by YAP, which has significant implications for our understanding of Hippo pathway regulation, YAP-isoform specific signaling, and the role of these proteins in cell proliferation, apoptosis, and tumorigenesis.
authors.affiliation: From the School of Chemistry and Biochemistry, University of Western Australia, WA 6009, Australia, Department of Physiology, NUS Yong Loo Lin School of Medicine and Mechanobiology Institute (MBI), National University of Singapore, Singapore 117411, and phsmlf@nus.edu.sg.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Finch-Edmondson
authors.affiliation: From the School of Chemistry and Biochemistry, University of Western Australia, WA 6009, Australia, Centre for Medical Research, The Harry Perkins Institute of Medical Research, WA 6009, Australia.
authors.forename: Robyn P
authors.initials: RP
authors.lastname: Strauss
authors.affiliation: From the School of Chemistry and Biochemistry, University of Western Australia, WA 6009, Australia, Centre for Medical Research, The Harry Perkins Institute of Medical Research, WA 6009, Australia.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Passman
authors.affiliation: Department of Physiology, NUS Yong Loo Lin School of Medicine and Mechanobiology Institute (MBI), National University of Singapore, Singapore 117411, and Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore 138673.
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
authors.affiliation: From the School of Chemistry and Biochemistry, University of Western Australia, WA 6009, Australia, Centre for Medical Research, The Harry Perkins Institute of Medical Research, WA 6009, Australia.
authors.forename: George C
authors.initials: GC
authors.lastname: Yeoh
authors.affiliation: From the School of Chemistry and Biochemistry, University of Western Australia, WA 6009, Australia, School of Health Sciences, The University of Notre Dame Australia, WA 6959, Australia.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Callus
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; C517794:Wwtr1 protein, mouse; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex
keywords: Hippo pathway; glycogen synthase kinase 3 (GSK-3); post-transcriptional regulation; protein degradation; transcriptional coactivator with PDZ-binding motif (TAZ); yes-associated protein (YAP)