Dev Cell. 2020 Jan 6;52(1):104-117.e5.

José Ignacio Valenzuela¹, Franck Perez²

1. Institut Curie, PSL Research University, CNRS, UMR144, 26 rue d'Ulm, 75005 Paris, France. Electronic address: jose-ignacio.valenzuela@curie.fr.
2. Institut Curie, PSL Research University, CNRS, UMR144, 26 rue d'Ulm, 75005 Paris, France. Electronic address: franck.perez@curie.fr.

Abstract

Ephrins can elicit either contact-mediated cell-cell adhesion or repulsion, depending on the efficiency of the removal of their ligand-receptor complexes from the cell surface, thus controlling tissue morphogenesis and oncogenic development. However, the dynamic of the turnover of 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 the filopodia, at cell-to-cell contacts. Clusters of ephrin-A1 from donor cells surf on filopodia associated to EphA2-bearing subdomains of acceptor cells. Full-length ephrin-A1 is transferred to acceptor cells by trans-endocytosis through a proteolysis-independent 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.

Presented by José Ignacio Valenzuela