Adherens junctions formation and roles of p120ctn in intestinal homeostasis during enterocytic differentiation
During intestinal differentiation, epithelial cells modify their shape and genes activities in response to environmental signals. In particular, intestinal cells modulate their cell-matrix and cell-cell adhesion through protein complexes associated with integrins and cadherins respectively. Using the human adenocarcinoma cell line HT-29, we study adherens junction's formation along enterocytic differentiation and we highlight key factors implicated in the successive steps that allow the maturation of these junctions. We show that laminine 5 induces an increase in E-cadherin expression and allows the initiation of adherent junction's assembly through cell -matrix adhesion: laminine 5 - dependent activation of α3β1 and α6β4 integrins induces a transitional activation of PI3 Kinase that activates monomeric GTPAses Rac1 and its variant Rac1b. Then we show that adherens junction maturation is favoured by lipid rafts emergence. p120ctn interacts preferentially with E-cadherin in lipid rafts and their recruitment into this fraction is Rac1-dependent. Furthermore this process is correlated with epithelial cell differentiation. In a second part, we describe a new function of p120ctn in intestinal cells homeostasis. We show that the increase in p120ctn cytoplasmic level induces a downregulation of HT-29 cells proliferation. This effect result from the interaction of p120ctn with the cyclin E / cdk2 complex in the centrosome which leads to cyclin E overexpression. This process leads to centrosome overduplication , a phenomenon often observed in tumor cells.