Models for the regulation of EphB–ephrinB endocytosis. (A) EphB2 trans-endocytosis into ephrinB⁺ cells requires Tiam2, activating Rac subfamily GTPases leading to actin cytoskeleton rearrangement and ligand–receptor internalization. Direct interaction between ephrinBs and Tiam2 has previously been established (Terawaki et al., 2010). (B) EphB2-Fc soluble uptake into ephrinB⁺ cells does not require Rac or Tiam but is negatively regulated by RhoA subfamily GTPases. (C) EphrinB trans-endocytosis into EphB2⁺ cells uses a similar mechanism to EphB2 trans-endocytosis. (D) EphrinB2-Fc uptake into EphB2⁺ cells is dependent on both Tiam and Vav family GEFs and Rac activity (Tanaka et al., 2004; Cowan et al., 2005; Tolias et al., 2007).