Dynamic regulation of adherens junctions: Implication in cell differentiation and tumor development

Abstract

Adherens junctions (AJ) are fundamental cellular subcompartments required for the integrity of animal tissues and organs. The core complex of AJ is formed of transmembrane cell-cell adhesion molecules, cadherins, and adaptor, the catenins that link the complex to cytoskeletal and regulatory networks in the cell. Clustering of these molecules at junctions induces signaling pathways that regulate cellular responses, with crucial effects on the physiology and pathology of the epithelium, from cell differentiation to tumor development. Loss of E-cadherin expression is a hallmark of epithelial-to-mesenchymal transition (EMT), the process allowing the dissemination and the invasion of metastatic tumors. In this chapter, we focus on intestinal epithelium to highlight how cell-cell junction proteins, especially AJ proteins, interact together in normal and cancerous contexts to regulate major cellular processes such as cell differentiation and migration. For instance, imbalance in the signaling properties of catenins results in cell cycle deregulation during cancer and metastasis. We will also describe signaling and trafficking machineries that drive dynamic regulation of AJ and how these mechanisms are co-opted in cancer. In particular, the crosstalk between AJ, polarity proteins, extracellular matrix and microenvironment will be discussed. Recent evidences indicate that cell-cell junctions modulate chromatin function and mutually, we will also discuss epigenetic mechanisms that regulate AJ. Finally, we will examine more recent hypotheses about AJ implications in cancer stem cells and give an overview of cancer therapies that target cell-cell junction proteins.