Could beta-catenin regulate the expression of proteolitic enzymes during angiogenesis?

Abstract

During angiogenesis several modifications occurs at endothelial cell plasma membrane level as: MT-MMPs and serine integral membrane proteases (SIMPs) over-expression. Moreover, when endothelial cells during angiogenesis acquired a mesenchymal phenotype the cell-cell interactions mediate by cadherins are lost and β-catenin, a stabilizer of interaction occurring between cadherins and cytoscheleton, can translocate to the nucleus where acts as transcription factor in association to TCF/LEF. Our experiments were focalized to the expression/activation of proteolytic enzymes when cell-cell contacts are perturbed, by mechanical or site specific perturbations. We have analyzed the mRNA, proteins and enzymatic activities of several proteases when endothelial cell-cell contacts are mechanically or by antibodies [against cadherins domains (Cac125 and Pan-cad)] addition perturbed. A computational approach have shows that the binding sequences hTBE-1 and hTBE-2, described as MMP-7’s regulation sequences, are present in all proteolytic enzyme in 5’non translated 50.000 bp analyzed sequences. These observations were confirmed by experiments in which synthetic oligonucleotides recognizing the DNA binding sequences of the complex b-catenin/TCF-4 compete about proteolytic enzymes expression. Our results show a possible relationship between proteases expression and cell-cell contact stabilization; they strongly suggest a role played by β-catenin-TCF/LEF complex as proteolityc enzyme genes regulatory element.