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Molecular and Cellular Biology, April 2008, p. 2426-2436, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.01874-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

TAZ Promotes Cell Proliferation and Epithelial-Mesenchymal Transition and Is Inhibited by the Hippo Pathway{triangledown}

Qun-Ying Lei,1,2* Heng Zhang,2 Bin Zhao,4 Zheng-Yu Zha,2 Feng Bai,5 Xin-Hai Pei,5 Shimin Zhao,2,3 Yue Xiong,2,5* and Kun-Liang Guan2,4

Department of Biological Chemistry, School of Medicine,1 Molecular and Cellular Biology Laboratory, Institutes of Biomedical Sciences,2 Department of Biology, School of Life Science Fudan University, Shanghai 200032, China,3 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093,4 Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275995

Received 15 October 2007/ Returned for modification 17 November 2007/ Accepted 14 January 2008

TAZ is a WW domain containing a transcription coactivator that modulates mesenchymal differentiation and development of multiple organs. In this study, we show that TAZ is phosphorylated by the Lats tumor suppressor kinase, a key component of the Hippo pathway, whose alterations result in organ and tissue hypertrophy in Drosophila and contribute to tumorigenesis in humans. Lats phosphorylates TAZ on several serine residues in the conserved HXRXXS motif and creates 14-3-3 binding sites, leading to cytoplasmic retention and functional inactivation of TAZ. Ectopic expression of TAZ stimulates cell proliferation, reduces cell contact inhibition, and promotes epithelial-mesenchymal transition (EMT). Elimination of the Lats phosphorylation sites results in a constitutively active TAZ, enhancing the activity of TAZ in promoting cell proliferation and EMT. Our results elucidate a molecular mechanism for TAZ regulation and indicate a potential function of TAZ as an important target of the Hippo pathway in regulating cell proliferation tumorigenesis.

* Corresponding author. Mailing address for Qun-Ying. Lei: Department of Biological Chemistry, School of Medicine, Molecular and Cellular Biology Laboratory, Institutes of Biomedical Sciences, Department of Biology, School of Life Science, Fudan University, Shanghai 200032, China. Phone: 86-21-5423-7834. Fax: 86-21-5423-7450. E-mail: qlei{at}fudan.edu.cn. Mailing address for Yue Xiong: Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. Phone: (919) 962-2142. Fax: (919) 966-8799. E-mail: yxiong{at}email.unc.edu

{triangledown} Published ahead of print on 28 January 2008.

Molecular and Cellular Biology, April 2008, p. 2426-2436, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.01874-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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