Figure 2.

Clathrin-mediated endocytosis (CME) and endocytic trafficking in the control of E-cadherin dynamics. (A) Binding of p120CTN to the juxta-membrane region of the cytoplasmic tail of E-cadherin prevents the recruitment of endocytic adaptors favoring the stabilization of E-cadherin at the plasma membrane. Alternative recruitment of clathrin adaptors to the same region promotes CME of E-cadherin (105). (B) The adaptor AP-2 induces CME by displacement of p120CTN (105). (C,D) The endocytic protein NUMB may also drive internalization by serving as a scaffold between E-cadherin (or p120CTN) and the canonical endocytic adaptors, AP-2 and EPS15 (107, 108). NUMB may act either by (C) bridging together p120 and endocytic adaptors, thereby promoting the internalization of the entire E-cadherin/p120CTN complex or by (D) binding directly to the NVYY motif in E-cadherin, thus facilitating the internalization of p120-unbound E-cadherin, ultimately opposing p120CTN-mediated suppression of endocytosis (107, 108). (E) Activated SRC promotes the phosphorylation of E-cadherin enabling the binding of the ubiquitin ligase HAKAI, which induces CME, and the subsequent degradation of E-cadherin via the lysosomal route (98). Junctional activation of SRC, dependent on the endocytic F-BAR-containing protein CIP4, is also required to increase junctional tension across E-cadherin (not depicted): an event that facilitates junction dismantling and E-cadherin endocytosis (109). Following clathrin-coated vesicles (CCVs)-mediated internalization, E-cadherin can traffic through different routes, regulated by a diverse set of molecular determinants, which determine E-cadherin fate either to lysosomal-mediated degradation or late endosomal recycling back to the lateral junction, in a process that fuels AJ dynamics and the remodeling necessary for epithelial tissues homeostasis (110).