title: Mechanism of action of a WWTR1(TAZ)-CAMTA1 fusion oncoprotein.
abstract: The WWTR1 (protein is known as TAZ)-CAMTA1 (WC) fusion gene defines epithelioid hemangioendothelioma, a malignant vascular cancer. TAZ (transcriptional coactivator with PDZ binding motif) is a transcriptional coactivator and end effector of the Hippo tumor suppressor pathway. It is inhibited by phosphorylation by the Hippo kinases LATS1 and LATS2. Such phosphorylation causes cytoplasmic localization, 14-3-3 protein binding and the phorphorylation of a terminal phosphodegron promotes ubiquitin-dependent degradation (the phosphorylation of the different motifs has several effects). CAMTA1 is a putative tumor suppressive transcription factor. Here we demonstrate that TAZ-CAMTA1 (TC) fusion results in its nuclear localization and constitutive activation. Consequently, cells expressing TC display a TAZ-like transcriptional program that causes resistance to anoikis and oncogenic transformation. Our findings elucidate the mechanistic basis of TC oncogenic properties, highlight that TC is an important model to understand how the Hippo pathway can be inhibited in cancer, and provide approaches for targeting this chimeric protein.
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Robert J. Tomsich Pathology Institute, Lerner Research Institute, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Tanas
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: F O
authors.initials: FO
authors.lastname: Jadaan
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: C K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Robert J. Tomsich Pathology Institute, Lerner Research Institute, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Rubin
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D018323:Hemangioendothelioma, Epithelioid / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D014162:Transfection
chemical_list: C487554:CAMTA1 protein, human; D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human