The cytoplasmic domain of classical cadherins is

The cytoplasmic domain of classical cadherins is highly conserved and can interact with different cytosolic proteins. Typically this domain is associated with catenin family members, including p120 catenin, β-catenin, and α-catenin, which form a cadherin-catenin complex (Fig. 1). The catenin family proteins are involved in the regulation of different cell-signaling pathways, for example, p120 catenin binds to the juxtamembrane region of cadherins, stabilizes cadherins by masking an endocytic signal conserved in classical cadherins, and also regulates the Annexin V-Cy5 Apoptosis Kit australia cytoskeleton through Rho GTPases [20,30]. Besides binding to cadherins, p120 catenin has also been reported to shuttle into the nucleus and interact with the transcription factor Kaiso that is involved in regulating the expression of a series of cancer-related genes [31]. β-catenin, another catenin family member that binds to cadherins, has been well-studied as a nuclear transcriptional co-activator for the lymphoid enhancer-binding factor-1 (LEF-1)/T-cell factor (TCF) family of transcription factors, and it is an important functional protein in Wnt signaling pathways [32]. Besides the APC-β-catenin complex, E-cadherin binding is another important mechanism that can regulate Wnt signaling pathways. E-cadherin binding to β-catenin can prevent β-catenin nuclear localization and β-catenin/LEF-1-mediated transactivation. Alternatively, destabilization of the cadherin complex will release β-catenin and can lead to the activation of Wnt signaling pathways. Moreover, α-catenin, also associated with cadherins, has been reported to be involved in Hippo signaling pathways by interacting with yes-associated protein 1 (YAP1). α-Catenin association with YAP1 prevents YAP1 nuclear localization [33]. Therefore, besides mediating cell-cell adhesion, cadherins can also affect many different signaling pathways through their binding partners. The Rho family of small GTPases is a group of proteins that impact a wide variety of cell functions such as cell movement and mitosis [34]. Rho GTPases consist of three major members, RhoA, Rac1, and Cdc42. These proteins, similar to other GTPases, can be converted to the active GTP-bound form by guanine nucleotide exchange factors (GEFs), and GTPase activity can be stimulated by GTPase-activating proteins (GAPs). Moreover, guanine nucleotide dissociation inhibitors (GDIs) sequester GTPases in their inactive form. Rho GTPases have been reported to be closely regulated by the cadherin and catenin protein families, for example, cytosolic p120 catenin that does not bind to cadherin can directly inhibit the activity of RhoA by functioning as a GDI thus sequestering RhoA in the inactive form [30,35].
Cadherin switching and effects of inappropriate cadherin expression Epithelial cells typically express E-cadherin, endothelial cells typically express VE-cadherin, while mesenchymal cells express mesenchymal types of cadherins, including N-cadherin, R-cadherin, and cadherin-11. Under physiological differentiated states, cells tend to express specific cadherin proteins to maintain cell polarity and tissue integrity. However, under certain circumstances, including pathological conditions such as cancer, cells express “inappropriate cadherins” [36]. In cancer, a hallmark of EMT is the disruption of adherens junctions [37]. When epithelial cancer cells undergo EMT, they switch from expressing E-cadherin to expressing a mesenchymal type of cadherins, such as N-cadherin, P-cadherin, R-cadherin, T-cadherin, and cadherin 11. This process is called cadherin switching [4]. Importantly, the downregulation of E-cadherin and upregulation of mesenchymal cadherins does not always happen at the same time. For example, in some cases, E-cadherin expression does not change, while N-cadherin expression is elevated [12]. However, the expression of inappropriate mesenchymal cadherins is sufficient to have a significant impact on cancer cell behavior. Developmentally, EMT and cadherin switching are early events during embryogenesis, which allow selected populations of cells in the embryo to delaminate from cell nests [2]. For example, during gastrulation, when epiblast cells ingress through the primitive streak and neural crest cells emigrate from the neural tube. In a similar fashion, cancer cells gain the capacity to disrupt tissue integrity and migrate from their original position. Many research groups have shown that N-cadherin increases motility in cancer cells regardless of E-cadherin expression [[38], [39], [40]]. As mentioned earlier, EC1 and EC2 domains of cadherins form a “minimal essential unit” for homophilic cell-cell adhesion while EC3–5 contribute to cell adhesion and have additional functions beyond adhesion. A major difference between E-cadherin and N-cadherin has been reported to be located in EC4. A 69 amino acid-portion of EC4 of N-cadherin was shown to promote EMT in squamous epithelial cells and increase cell motility [41]. Moreover, EC4 of N-cadherin interacts with fibroblast growth factor receptor (FGFR), forming a complex that can facilitate cell motility, invasion, and metastasis through FGFR signaling [42]. In addition, the scaffolding molecule Na+/H+ exchanger regulatory factor (NHERF) links the N-cadherin/β-catenin complex to platelet-derived growth factor receptor (PDGFR), which can modulate the actin cytoskeleton and regulate cell motility [43]. Therefore, when tumor cells upregulate N-cadherin expression, they also gain the ability to activate multiple growth factor receptor signaling pathways that can promote cell growth and metastasis. In contrast, E-cadherin has been reported to interact with or regulate different growth factor receptors, but these interactions typically result in a decrease in growth factor receptor signaling. Receptors that have been reported to be inhibited by E-cadherin include FGFR, epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF1R) and hepatocyte growth factor receptor (HGFR) [[44], [45], [46], [47]]. Thus, cadherin switching can impact cancer cell behavior by affecting multiple growth factor signaling pathways, highlighting that cadherins are involved in more than just adhesion.