L'interaction entre les voies de signalisation TGF-B et Hippo : implication de la polarité apico-basale et de le protéine ZO-1

Abstract : Cell-cell contacts drive signals controlling the process of contact inhibition, a phenomen on whereby normal cells grown in monolayers exhibit reduced proliferation, even growth arrest, when reaching confluency. This is in part due to the activation of the hippo pathway that drives the phosphorylation and nuclear exclusion of the transcriptional coactivators YAPand TAZ. This physiological process is crucial for the maintain of tissue homeostasis and it’soften lost during neoplastic progression or in vitro transformation.The transforming growth factor ß (TGF-ß) is a cytokine that also plays a pleiotropic role in homeostasis and carcinogenesis. Unlike The Hippo pathway, its canonical pathway is initiated by the activation of membrane receptors, which then phosphorylate the cytoplasmic transcription factors SMADs, leading to their nuclear translocation and the induction of TGF-ß target genes. Cell density and Hippo signaling have also been reported toblock TGF-ß responses, based on the ability of phospho-YAP/TAZ to sequester TGF-ßactivatedSMAD complexes in the cytoplasm. Thereby, my project’s aim was to investigate the interaction between the Hippo and the TGF-ß pathways in the context of cell density.In the first part of this study, we demonstrated that, although the activation of Hippopathway by cell density occurs in both epithelial and non-epithelial cells, the blocking of TGFßpathway only occurs in polarized epithelial cells. Furthermore, we provided evidence that epithelial cell polarization interferes with TGF-ß signaling well upstream and independent ofYAP/TAZ localization. Our results have led to the establishment of a new model specific topolarized epithelial cells where the sealing of the para-cellular permeability prevents theapicaly secreted TGF-ß ligand from accessing its receptors which are retained at the basolateral domain of the cytoplasmic membrane. In the second part of this work, based on the characterization of the biophysical parameters related to the barrier function of the epithelium, we demonstrated that the measurement of Trans-epithelial permeability (TER) could be used as a tool to monitor and verify the polarity of tight epithelia. Considering the involvement of tight junctions (TJs) in epithelial polarity, we examined the role of one of its cytoplasmic proteins, ZO-1. Our results showed that ZO-1is not required for either the TJs barrier or the fence functions in polarized EpH4 cells. Thus, we conclude that ZO-1 is not a good marker of fully polarized epithelial cells and is not essential for their resistance to apical TGF-ß
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Saber Ben Mimoun. L'interaction entre les voies de signalisation TGF-B et Hippo : implication de la polarité apico-basale et de le protéine ZO-1. Médecine humaine et pathologie. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCC231⟩. ⟨tel-02478724⟩

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