Contact inhibitory Eph signaling suppresses EGF-promoted cell migration by decoupling EGFR activity from vesicular recycling

Abstract

The ability of cells to adapt their behavior to growth factors in relation to their environment is an essential aspect of tissue development and homeostasis. Here we show that Eph receptor signaling from cell-cell contacts changes the cellular response to EGFR activation by altering its vesicular trafficking. Eph receptor activation traps EGFR in Rab5-positive early endosomes through an inhibition of Akt-dependent vesicular recycling. By altering the spatial distribution of EGFR activity during EGF stimulation, Eph receptor activation selectively suppresses migratory Akt signaling from the plasma membrane, while preserving proliferative ERK signaling from endosomes. We also show that soluble extracellular signals engaging the G-protein coupled receptor Kiss1 similarly suppress vesicular recycling to alter EGFR signaling. The cellular environment can thus modulate EGFR vesicular trafficking dynamics to generate context-dependent responses to EGF stimulation.\n\nSummaryEph receptor activation generates context-dependent cellular responses to EGFR activation by altering its vesicular trafficking dynamics.