Model for the role of rab5 in AP2 uncoating. Rab5 acts at multiple steps of the clathrin-coated vesicle cycle (red arrows). PtdIns(4,5)P₂ is the primary determinant for the recruitment of AP2 to the plasma membrane during coated pit assembly and this process is enhanced by μ2 phosphorylation, effected by AAK1 (1). Clathrin activates AAK1 to maximize cargo recruitment (2). After coated vesicle scission (3), clathrin is removed by the combined action of Hsc70 and auxilin. Recruitment of hRME-6 displaces AAK1, resulting in net μ2 dephosphorylation. Rab5 mediates PtdIns(4,5)P₂ turnover, resulting in efficient removal of AP2 and generation of an uncoated endocytic vesicle (4). There is therefore a mechanistic symmetry between AP2 assembly that requires PtdIns(4,5)P₂ and μ2 phosphorylation and disassembly that is mediated by μ2 dephosphorylation and a reduction in PtdIns(4,5)P₂. Both the latter processes are modulated by hRME-6/rab5.