Role of PIN1 in tissue renewal

点击翻译按钮获取中文摘要

The long-term objective of our research program is to provide comprehensive regulatory mechanisms accounting for the temporal and spatial orchestration of cell proliferation, differentiation and death needed to preserve tissue homeostasis. Phosphorylation is the most common post-translational modifications in cells. By modulating protein expression, localization and activity, phosphorylation plays a central role in orchestrating diverse cellular processes such as proliferation, differentiation and death. Although kinases and phosphatases performed a key role in converting an environmental cue into a timely response, post-phosphorylation regulatory mechanisms are now believe to play an as important task. In this regard, the peptidyl-prolyl cis/trans isomerase (PPIase) PIN1 is unique given that it is the only PPIase that recognizes phosphorylated proteins. Some PIN1 substrates have been identified and the spectrum of effects ranged from regulation of protein stability, phosphorylation, interaction, localization, enzymatic and transcriptional activity. Hence, PIN1 represents a unique player in post-phosphorylation regulatory mechanisms. The intestinal epithelium is an optimal model to study the dynamic of tissue renewal. Indeed, proliferative cells are restricted to crypts with daughter cells eventually being arrested in G0/G1 while beginning a differentiation program during their migration towards the top of the crypts. Differentiated cells are therefore mostly compartmentalized to the villi. This organized system is highly dynamic and the intestinal epithelium is renewed every 3-5 days. Studying for the first time the role of Pin1 in the rapid self-renewing intestine is a unique opportunity to provide novel instrumental cellular and molecular cues as to how cells orchestrate proliferation, differentiation and death to preserve tissue homeostasis (short-term objective). Two specific aims are proposed: 1) To analyze the impact of PIN1 loss on self-renewal capacity of the intestinal epithelium by using diverse models. 2) To identify PIN1 interacting partners and regulated proteins by performing the first systematic analysis of PIN1 interacting partners and regulated proteins by quantitative proteomics. Altogether, by analyzing the impact of PIN1 depletion on tissue homeostasis, dissecting PIN1 contribution in specific cellular processes (proliferation, differentiation, death) and exposing PIN1 relevant targets, our unique research program will advance our knowledge on the contribution of prolyl isomerization of phospho-proteins in tissue homeostasis and regeneration. Also, by exploiting diverse models that recapitulate the different steps leading to a functional tissue, our results may reflect a more dynamic, integrated and relevant context that will assist tissue engineers in optimizing tissue regeneration conditions.