The endocytosis of E-cadherin has recently emerged as an important determinant 
of cadherin function with the potential to participate in remodeling adhesive 
contacts. In this study we focused on the initial fate of E-cadherin when it 
predominantly exists free on the cell surface prior to adhesive binding or 
incorporation into junctions. Surface-labeling techniques were used to define 
the endocytic itinerary of E-cadherin in MCF-7 cells and in Chinese hamster 
ovary cells stably expressing human E-cadherin. We found that in this 
experimental system E-cadherin entered a transferrin-negative compartment before 
transport to the early endosomal compartment, where it merged with classical 
clathrin-mediated uptake pathways. E-cadherin endocytosis was inhibited by 
mutant dynamin, but not by an Eps15 mutant that effectively blocked transferrin 
internalization. Furthermore, sustained signaling by the ARF6 GTPase appeared to 
trap endocytosed E-cadherin in large peripheral structures. We conclude that in 
isolated cells unbound E-cadherin on the cell surface is predominantly 
endocytosed by a clathrin-independent pathway resembling macropinocytotic 
internalization, which then fuses with the early endosomal system. Taken with 
earlier reports, this suggests the possibility that multiple pathways exist for 
E-cadherin entry into cells that are likely to reflect cell context and 
regulation.