Interaction of the Adherens Junctions with RNA Complexes in Cell Behavior and Disease
Research in the Kourtidis Lab focuses on fully understanding: a) a novel interaction of the adherens junctions with the RNA interference (RNAi) machinery and other RNA-associated complexes, and b) the role of this mechanism in cell behavior and disease.
Cell-cell junctions and RNA complexes are having an intimate affair...
The adherens junctions are cell-cell adhesion structures critical for the development and maintenance of the tissue architecture. Disruption of adherens junctions results in loss of tissue integrity and has been associated with numerous diseases, including cancer. Work to shed light into the mechanisms through which the adherens junctions influence cell behavior led us to the discovery of a novel interaction with the RNAi machinery.
We have shown that cadherin complexes recruit the microprocessor and RNA-induced silencing (RISC) complexes, as well as specific sets of miRNAs and mRNAs. By recruiting RNAi, mature cadherin junctions regulate processing and activity of miRNAs to suppress expression of promoters of cellular transformation. This was a breakthrough finding that challenged the prevailing dogma that the microprocessor functions solely in the cell nucleus and the RISC in the cytoplasm. Work in our lab now portrays an extensive cross-talk between cadherin junctions and RNA-protein complexes, revealing a new epicenter of RNA regulation in the cell.
...that impacts cell behavior...
Our data show that disruption of the cadherin-associated RNAi complex results in compromised epithelial integrity, decreased miRNA levels and activity, upregulation of a number of growth-promoting mRNAs, and increased anchorage-independent growth, a hallmark of epithelial cell transformation. We also find dysregulation of this mechanism in diseased tissues. Together, these findings suggest a key role of this mechanism in the maintenance of the normal epithelial phenotype.
...and opens numerous directions of investigation
Our work bridges the fields of cell-cell adhesion and RNA biology and introduces a novel area of research, while also posing numerous new questions: how is this mechanism regulated; which is the full spectrum of the molecules involved? what is the role of this mechanism in normal cell physiology and homeostasis? what is its implication in disease, particularly in tumorigenesis? can this mechanism be exploited for therapeutic intervention? By employing cutting-edge approaches, including super-resolution microscopy, CRISPR/Cas9-generated in vitro and in vivo models, 3D cultures, and next generation sequencing, we are systematically addressing these questions in our lab, through a number of ongoing projects.