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

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.

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

“…As the acquisition of a motile and tumorigenic phenotype with low proliferative activity is a feature of cells showing epithelial to mesenchymal transition, and TAZ expression promotes epithelial to mesenchymal transition in other tumors, 16,18,27-30 we assessed whether TAZ expression was associated with modifications of epithelial to mesenchymal transition features in endometrial cancer cells. The expression of a set of previously described epithelial to mesenchymal transition-related genes 8 was evaluated in both types of endometrial cancer clones and we found that some epithelial to mesenchymal transition genes were expressed more strongly in Ishikawa-TAZ cells, such as SNAI1 (Po0.001), SNAI2 (Po0.001), and HMGA2 (Po0.05: Figure 3a).…”

“…14 Dysregulation of the Hippo pathway is correlated with epithelial to mesenchymal transition and cancer development, mainly driven by TAZ and YAP. 15 These two DNA-binding proteins are normally repressed by Mst2 and Lats2 phosphorylation, 16,17 or they are regulated by the expression and location of the cell polarity protein Scribble. 18 TAZ/YAP and epithelial to mesenchymal transition are thought to maintain a bidirectional relationship, whereby the loss of polarity and cell contacts (key events during the epithelial to mesenchymal transition process) induces the activation of both factors, which in turn participate in the epithelial to mesenchymal transition program.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Activated Lats1/2 in turn phosphorylate YAP/TAZ transcription co-activators on several residues (Dong et al, 2007;Zhao et al, 2007;Hao et al, 2008;Lei et al, 2008;Oka et al, 2008). Phosphorylation of S127 in YAP promotes 14-3-3 binding, resulting in cytoplasmic sequestration and therefore inactivation of YAP (Dong et al, 2007;Zhao et al, 2007;Hao et al, 2008;Lei et al, 2008;Oh and Irvine, 2008). Indeed, mutation of S127 and disruption of 14-3-3 binding lead to activation of YAP (Zhao et al, 2007), confirming the inhibitory nature of this phosphorylation.…”

“…Nevertheless, in another report comparing cell attachment on stiff matrix or complete detachment, the Hippo pathway kinases Lats1/2 were found to be activated by cell detachment, also in a cytoskeleton-dependent manner . It is well established that Lats1/2 directly phosphorylate YAP/TAZ and trigger their cytoplasmic translocation (Zhao et al, 2007;Lei et al, 2008). Therefore it would be important to clarify whether Lats1/2 are mediating mechanical response of YAP/ TAZ, and if not, what is the mechanism underlying YAP/TAZ regulation in this context.…”

“…The EMT program was known to elicit stem cell properties from epithelial cells (Mani et al, 2008). And both TAZ and YAP have been shown to induce EMT in cultured mammary epithelial cells (Overholtzer et al, 2006;Lei et al, 2008). Interestingly, induction of EMT by other transcription regulators of EMT such as Twist also elevated TAZ expression .…”