Research in our 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 regulating cell behavior in normal and diseased tissues.
The adherens junctions are critical cell-cell adhesion structures, playing a fundamental role in the development and maintenance of the normal tissue architecture. E-cadherin is the core adhesion receptor in epithelial tissues and is stabilized through its association with the catenin family of proteins, such as p120 catenin (p120). Disruption of adherens junctions results in loss of tissue integrity and has been associated with numerous diseases, including cancer. It has been also shown that it results in aberrant cell behavior. In an effort to clarify the mechanism through which the adherens junctions influence cell behavior, we recently discovered a novel association with the RNAi machinery. We have shown that PLEKHA7, a new E-cadherin - p120 partner, recruits the microprocessor and RNA-induced silencing (RISC) complexes at the adherens junctions. The microprocessor is an integral component of the RNAi machinery that catalyzes the first step of miRNA biogenesis through its core members DROSHA and DGCR8. Until recently, the microprocessor was thought to localize solely in the cell nucleus, however, our work revealed a functional microprocessor at the junctions of differentiated epithelial cells. PLEKHA7 also recruits the core (Ago2, GW182, PABPC1) and several accessory components of RISC, as well as specific sets of miRNAs and mRNAs. RISC catalyzes the miRNA-mediated silencing of mRNAs. By recruiting the microprocessor and RISC, PLEKHA7 promotes processing and function of a set of miRNAs to suppress expression of several regulators of cellular transformation. Our findings revealed co-localization of RNAi complexes, miRNAs, and mRNAs at the epithelial adherens junctions, suggesting for a new epicenter of RNA regulation and a localized function of the RNAi machinery, which has previously gone unnoticed. Importantly, PLEKHA7 depletion results in compromised epithelial integrity, loss of junctional localization and decreased activity of the microprocessor and RISC, decreased miRNA levels and activity, upregulation of a number of growth-promoting mRNAs, and increased anchorage-independent growth, a hallmark of cellular transformation. Taken together, these results identified a direct link between cell-cell adhesion, epithelial integrity and cell behavior, through RNAi and bridged for the first time the fields of cell-cell adhesion and RNA biology, introducing a new area of investigation.
By employing cutting-edge approaches, such as super-resolution microscopy, proteomics, fluorescent in-situ hybridization, RNA-CLIP, and next generation sequencing, we are now discovering an extensive interaction of the adherens junctions with RNA complexes, mRNAs, miRNAs and non-coding RNAs. Elucidating all the molecular details of this mechanism and its role in regulating cell behavior is the main goal of our research. We are particularly interested in investigating the implications of this mechanism in several diseases, such as in cancer. Numerous questions also emerge regarding the physiological role of this mechanism in normal tissue physiology. Several projects that stem from the above findings are currently in progress or are being initiated in our lab.