Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
14-3-3 Proteins / physiology
-
Acyltransferases
-
Amino Acid Motifs
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / physiology
-
Cell Division
-
Cell Line, Tumor
-
Cell Movement
-
Cell Transdifferentiation / physiology
-
Cell Transformation, Neoplastic
-
Conserved Sequence
-
Drosophila Proteins / genetics
-
Drosophila Proteins / physiology
-
Epithelial Cells / cytology
-
Humans
-
Membrane Proteins / genetics
-
Membrane Proteins / physiology
-
Mesoderm / cytology
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / physiology
-
Nuclear Proteins / physiology
-
Phosphorylation
-
Protein Processing, Post-Translational / physiology*
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / physiology*
-
Proteins / genetics
-
Proteins / physiology*
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / physiology
-
Receptor Protein-Tyrosine Kinases / genetics
-
Receptor Protein-Tyrosine Kinases / physiology
-
Recombinant Fusion Proteins / physiology
-
Serine-Threonine Kinase 3
-
Transcription Factors / genetics
-
Transcription Factors / physiology*
-
Transcription, Genetic
-
Transferases (Other Substituted Phosphate Groups) / genetics
-
Transferases (Other Substituted Phosphate Groups) / physiology
-
c-Mer Tyrosine Kinase
Substances
-
14-3-3 Proteins
-
Cell Cycle Proteins
-
Drosophila Proteins
-
Membrane Proteins
-
Nerve Tissue Proteins
-
Nuclear Proteins
-
Proteins
-
Proto-Oncogene Proteins
-
Recombinant Fusion Proteins
-
SAV1 protein, human
-
Transcription Factors
-
YY1AP1 protein, human
-
ex protein, Drosophila
-
Acyltransferases
-
TAFAZZIN protein, human
-
MERTK protein, human
-
Receptor Protein-Tyrosine Kinases
-
c-Mer Tyrosine Kinase
-
Protein Serine-Threonine Kinases
-
STK3 protein, human
-
Serine-Threonine Kinase 3
-
SGMS1 protein, human
-
Transferases (Other Substituted Phosphate Groups)