Localized intercellular transfer of ephrin-As by trans-endocytosis enables long-term signaling

José Ignacio Valenzuela (1) , Franck Perez (1)

1 Biologie Cellulaire et Cancer

Ephrins can elicit either contact-mediated cell-cell adhesion or repulsion, depending on the efficiency of removal of their ligand/receptor complexes from the cell surface, thus controlling tissue morphogenesis and oncogenic development. However, the dynamic of turnover of the newly assembled ephrin/Eph complexes during cell-cell interactions remains mostly unexplored. Here we show that ephrin-A1/EphA2 complexes are locally formed at the tip of filopodia, at cell-to-cell contacts. Clusters of ephrin-A1 from donor cells surf on filopodia associated to EphA2-bearing sub-domains of acceptor cells. Fulllength ephrin-A1 is transferred to acceptor cells by trans-endocytosis through a proteolysisindependent mechanism. Trans-endocytosed ephrin-A1 bound to its receptor enables signaling to be emitted from endo-lysosomes of acceptor cells. Localized trans-endocytosis of ephrin-A1 sustains contact-mediated repulsion on cancer cells. Our results uncover the essential role played by local concentration at the tip of filopodia and the trans-endocytosis of full-length ephrin to maintain long-lasting ephrin signaling.

Domaines: Sciences du Vivant [q-bio]; Biologie cellulaire; Cancer

José Ignacio Valenzuela, Franck Perez. Localized intercellular transfer of ephrin-As by trans-endocytosis enables long-term signaling. Developmental Cell, 2020, 52 (1), pp.104-117.e5. ⟨10.1016/j.devcel.2019.11.013⟩. ⟨hal-03090958⟩