Research ArticleCell Biology

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

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Science Signaling  31 Jul 2018:
Vol. 11, Issue 541, eaat0114
DOI: 10.1126/scisignal.aat0114

Limiting movement in a crowded situation

The epidermal growth factor receptor (EGFR) mediates the distinct cellular processes of proliferation and migration, which do not always occur concomitantly upon EGFR stimulation. Eph receptors are activated by increasing cell density, and they suppress cell migration, in contrast to EGFR. Stallaert et al. (see also the Focus by Shi and Wang) found that Eph receptors selectively inhibited migration but not proliferation mediated by EGFR. Eph receptor activation prevented the recycling of EGFR to the cell surface (the subcellular compartment from where it mediates migratory signaling) by trapping EGFR in endosomes (the subcellular compartment from where it can continue to promote proliferative signaling). In addition, EGFR-mediated migration was also inhibited by the receptor Kiss1, which not only is structurally unrelated to Eph receptors but also inhibits cell migration by suppressing EGFR recycling. The authors note that this system enables different receptors to regulate a signaling pathway without needing to directly interact with components in that pathway.


The ability of cells to adapt their response to growth factors in relation to their environment is an essential aspect of tissue development and homeostasis. We found that signaling mediated by the Eph family of receptor tyrosine kinases from cell-cell contacts changed the cellular response to the growth factor EGF by modulating the vesicular trafficking of its receptor, EGFR. Eph receptor activation trapped EGFR in Rab5-positive early endosomes by inhibiting Akt-dependent vesicular recycling. By altering the spatial distribution of EGFR activity, EGF-promoted Akt signaling from the plasma membrane was suppressed, thereby inhibiting cell migration. In contrast, ERK signaling from endosomal EGFR was preserved to maintain a proliferative response to EGF stimulation. We also found that soluble extracellular signals engaging the G protein–coupled receptor Kiss1 (Kiss1R) similarly suppressed EGFR vesicular recycling to inhibit EGF-promoted migration. Eph or Kiss1R activation also suppressed EGF-promoted migration in Pten−/− mouse embryonic fibroblasts, which exhibit increased constitutive Akt activity, and in MDA-MB-231 triple-negative breast cancer cells, which overexpress EGFR. The cellular environment can thus generate context-dependent responses to EGF stimulation by modulating EGFR vesicular trafficking dynamics.

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