Mechanism of action of a WWTR1(TAZ)-CAMTA1 fusion oncoprotein

M R Tanas; S Ma; F O Jadaan; C K Y Ng; B Weigelt; J S Reis-Filho; B P Rubin

doi:10.1038/onc.2015.148

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Mechanism of action of a WWTR1(TAZ)-CAMTA1 fusion oncoprotein

Journal article

Open access

Peer reviewed

Mechanism of action of a WWTR1(TAZ)-CAMTA1 fusion oncoprotein

M R Tanas, S Ma, F O Jadaan, C K Y Ng, B Weigelt, J S Reis-Filho and B P Rubin

Oncogene, Vol.35(7), pp.929-938

02/18/2016

DOI: 10.1038/onc.2015.148

PMCID: PMC4983459

PMID: 25961935

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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.

Transfection

Mutagenesis, Site-Directed

Humans

Reverse Transcriptase Polymerase Chain Reaction

Blotting, Western

Animals

Cell Transformation, Neoplastic - genetics

Oncogene Proteins, Fusion - genetics

Hemangioendothelioma, Epithelioid - genetics

Fluorescent Antibody Technique

HEK293 Cells

Trans-Activators - genetics

Mice

Intracellular Signaling Peptides and Proteins - genetics

3T3 Cells

Calcium-Binding Proteins - genetics

Details

Title: Subtitle: Mechanism of action of a WWTR1(TAZ)-CAMTA1 fusion oncoprotein
Creators: M R Tanas - Robert J. Tomsich Pathology Institute, Lerner Research Institute, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
S Ma - Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
F O Jadaan - Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
C K Y Ng - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
B Weigelt - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
J S Reis-Filho - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
B P Rubin - Robert J. Tomsich Pathology Institute, Lerner Research Institute, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
Resource Type: Journal article
Publication Details: Oncogene, Vol.35(7), pp.929-938
Publisher: England
DOI: 10.1038/onc.2015.148
PMID: 25961935
PMCID: PMC4983459
ISSN: 0950-9232
eISSN: 1476-5594
Grant note: U54CA168512 / NCI NIH HHS P30 CA008748 / NCI NIH HHS U54 CA168512 / NCI NIH HHS
Language: English
Date published: 02/18/2016
Academic Unit: Pathology
Record Identifier: 9984047614702771

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