br Introduction Epithelial mesenchymal transition EMT
Introduction Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial myosin lose cell polarity and cell-cell adhesion, and gain mesenchymal features with an increase of migratory and invasive properties . EMT is essential for mesoderm formation during embryo development and contributes to disease progression [2,3]. In this review, we focus on the process of cadherin switching that often occurs during EMT . Cadherin switching entails the change in the expression of cadherin type and typically results in a disruption of adherens junctions and a change of cellular behavior. Many signal transduction pathways can drive a cadherin switching event. The extracellular matrix (ECM) is the major noncellular compartment of tissues, including tumors, and is recognized to have important functions in cancer progression . Major components of the ECM include collagen, fibronectin, and laminin . The most abundant ECM constituent is collagen. Like many ECM proteins, collagen can mediate specific signaling pathways by binding to its receptors integrins and discoidin domain receptors (DDRs) [, , , ]. Recently, mechanisms of cadherin switching induced by collagen have been revealed [11,12]. DDRs, as major collagen receptors, have significant function in tumor progression and in mediating cadherin-switching events. In this review, we discuss the biological consequences of cadherin switching and how collagen drives this process through DDRs.
Adherens junctions and cadherins Cell-cell contact and adherence in tissues are organized, not random, phenomena [13,14]. Cell-cell junctions are of fundamental importance in the assembly of individual cells into tissues and the maintenance of tissue integrity. The cell-cell junctional complex includes tight junctions, adherens junctions, and desmosomes [15,16]. Adherens junctions are formed by cadherins and are critical in regulating the entire junctional complex of cell-cell contacts [17,18]. Typically, classical cadherins are transmembrane glycoproteins that mediate cell-cell adhesion via homophilic interaction of their extracellular domains in a calcium-dependent manner. They interact with the actin cytoskeleton by associating with catenins (p120, α and β) through their cytosolic domain [19,20]. Classical cadherins include E-cadherin (which is expressed in epithelial cells), N-cadherin (in neural tissue, muscle, and fibroblasts), R-cadherin (in the forebrain and bone), P-cadherin (in the basal layer of stratified epithelia) and VE-cadherin (in vascular endothelial cells) . These cadherins consist of an adhesive extracellular domain with five external cadherin (EC) repeats (EC1-EC5) and can be divided into two subtypes, type I and type II. Type I cadherins, which include E-cadherin, N-cadherin, R-cadherin, and P-cadherin, are different from type II cadherins, which include VE-cadherin, in that they have a highly conserved His-Ala-Val (HAV) tripeptide within the most distal EC repeat (EC1) that regulates homophilic adhesion . Interestingly, there is little evidence so far showing that the HAV motif is involved in directly mediating trans-cadherin interactions . However, synthetic peptides containing the HAV sequence can inhibit cadherin-based compaction . Studies have also shown that short cyclic HAV peptides such as ADH-1 (N-Ac-CHAVC-NH2) can inhibit N-cadherin function [25,26]. One possibility might be that the HAV motif mediates cis-cadherin interactions, which cooperate with trans-cadherin interactions to form an ordered junction structure . Besides the HAV sequence, it has also been reported that a conserved tryptophan residue within EC1 is required for trans-cadherin binding . EC2, although it does not mediate cell-cell adhesion directly, has been reported to form the “minimal essential unit” together with EC1 and is responsible for homophilic adhesion activity .