Eph receptor tyrosine kinases and their membrane-bound ephrin ligands control cell movement in several developing tissues. Activation of Eph receptors (EphBs) through cell-cell contact leads to cell-cell repulsion and separation. Although several pathways have been implicated in this process, the precise mechanisms are poorly defined. Evans et al. () establish a role for Ena/VASP – a family of cytoskeletal regulators – proteins downstream of Eph receptor signalling in Eph-mediated cell repulsion. Both soluble and substrate-bound ephrinB2 cause a repulsive response in neural tube explants by destabilising lamellipodia in the neural crest. The authors demonstrate that Ena/VASP proteins contribute to the destabilisation of neural crest lamellipodia and facilitate cell-cell repulsion at sites of ephrin activation. Ena/VASP-deficient fibroblasts display reduced repulsion in response to ephrin ligands. Moreover, Ena/VASP proteins localise to sites of Eph receptor activation and are required for internalisation of receptor-ligand complexes, which is necessary during Eph-mediated cell repulsion. This study provides significant insight into the mechanisms behind repulsive signalling and demonstrates a new link between Ephrin signalling and the Ena/VASP family.
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