Regulation of cadherin trafficking

Abstract

Cadherins are a large family of cell-cell adhesion molecules that tether cytoskeletal networks of actin and intermediate filaments to the plasma membrane. This function of cadherins promotes tissue organization and integrity, as demonstrated by numerous disease states that are characterized by the loss of cadherin-based adhesion. However, plasticity in cell adhesion is often required in cellular processes such as tissue patterning during development and epithelial migration during wound healing. Recent work has revealed a pivotal role for various membrane trafficking pathways in regulating cellular transitions between quiescent adhesive states and more dynamic phenotypes. The regulation of cadherins by membrane trafficking is emerging as a key player in this balancing act, and studies are beginning to reveal how this process goes awry in the context of disease. This review summarizes the current understanding of how cadherins are routed and how the interface between cadherins and membrane trafficking pathways regulates cell surface adhesive potential. Particular emphasis is placed on the regulation of cadherin trafficking by catenins and the interplay between growth factor signaling pathways and cadherin endocytosis.

Figure 1. Different Endocytic Pathways Utilized by E-cadherin

(A) Numerous studies have illustrated that classical cadherins, such as E-cadherin, can undergo various types of endocytic processing. Furthermore, the route taken by E-cadherin seems to be dependent on the presence of its cytoplasmic binding partner, β-catenin or p120. In the case of clathrin-mediated endocytosis, binding of β-catenin and p120 maintains E-cadherin’s association with the actin cytoskeleton network and prevents E-cadherin endocytosis. However, signaling events may cause disassociation between the cadherin and the catenins, thereby allowing adaptors, such as AP-2 and β-arrestin, to interact with the cytoplasmic tail and recruit clathrin and other accessory proteins that promote internalization. Once internalized, E-cadherin enters sorting/early endosomes in which other molecules proteins regulate the fate of the cadherin. GTPases, such as Rabs 5 and 7, as well as post-translational modification of the cadherin cytoplasmic tail (i.e. ubiquitination), promote E-cadherin entry into a lysosomal pathway for degradation. However, Rab 11 and the sorting nexin, SNX1, are essential for routing E-cadherin to recycling endosomes and ultimately back to the plasma membrane. (B) When E-cadherin undergoes clathrin-independent endocytosis, signaling events, such as Rac1 activation, are thought to rearrange the actin cytoskeleton network, allowing for internalization of the complex into early endosomes. This complex is internalized into a caveolin-enriched endosome and does not colocalize with markers for late endosomes or lysosomes, suggesting that the cadherin-catenin complex is then recycled back to the plasma membrane, with the assistance of the sorting nexin, SNX1.