TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway.
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.
Lei
Qun-Ying
QY
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. qlei@fudan.edu.cn
Zhang
Heng
H
Zhao
Bin
B
Zha
Zheng-Yu
ZY
Bai
Feng
F
Pei
Xin-Hai
XH
Zhao
Shimin
S
Xiong
Yue
Y
Guan
Kun-Liang
KL
D048948:14-3-3 Proteins / Q000502:physiology; D000217:Acyltransferases; D020816:Amino Acid Motifs; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D054338:Cell Transdifferentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008648:Mesoderm / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000502:physiology; D000076202:c-Mer Tyrosine Kinase; D000099317:Hippo Kinases
D048948:14-3-3 Proteins; D000217:Acyltransferases; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; D017855:Transferases (Other Substituted Phosphate Groups); D000076202:c-Mer Tyrosine Kinase; C415864:SAV1 protein, human; C456659:YY1AP1 protein, human; C085090:ex protein, Drosophila; C108675:TAFAZZIN protein, human; C097072:MERTK protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases; C455440:SGMS1 protein, human