Abstract
The Hippo (Hpo) pathway is a novel signaling pathway that controls organ size in Drosophila and mammals and is deregulated in a variety of human cancers. It consists of a set of kinases that, through a number of phosphorylation events, inactivate YAP, a transcriptional co-activator that controls cellular proliferation and apoptosis. We have identified PTPN14 as a YAP-binding protein that negatively regulates YAP activity by controlling its localization. Mechanistically, we find that the interaction of ectopic YAP with PTPN14 can be mediated by the respective WW and PPxY motifs. However, the PTPN14 PPxY motif and phosphatase activity appear to be dispensable for the negative regulation of endogenous YAP, likely suggesting more complex mechanisms of interaction and modulation. Finally, we demonstrate that PTPN14 downregulation can phenocopy YAP activation in mammary epithelial cells and synergize with YAP to induce oncogenic transformation.
Highlights
The Hippo (Hpo) pathway controls organ size by regulating cellular proliferation and apoptosis [1,2,3]
Endogenous YAP was immunoprecipitated from SF268 cells and prominent bands were excised from a Coommasie-stained gel and analyzed using mass spectrometry (MS) (Figure 1C)
The nature of the YAP-PTPN14 interaction has been studied in three previous reports, which indicate that the YAP-PTPN14 interaction is mediated by WW-PPxY binding [28,29,30]
Summary
The Hippo (Hpo) pathway controls organ size by regulating cellular proliferation and apoptosis [1,2,3]. The pathway was originally described in Drosophila and comprises several kinases that are conserved in mammals. Activation of the core mammalian pathway, consisting of MST-SAV and LATS-MOB complexes results in phosphorylation and inactivation of the transcriptional co-activator YAP and its family member TAZ, by means of cytoplasmic retention. Various proteins have been suggested to activate the pathway in response to contact inhibition. Members of adherens and tight junctions as well as proteins involved in cell polarity have recently been shown to regulate both YAP/TAZ activity and localisation as well as upstream components of the Hpo pathway, linking cell contact and polarity to cellular proliferation [8,9,10]
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