A microtubule arm regulates cell–cell repulsion, pointing hemocytes in opposite directions when they contact each other in Drosophila embryos.

Autocatalytic activation of epidermal growth factor receptor (EGFR) coupled to dephosphorylating activity of protein tyrosine phosphatases (PTPs) ensures robust yet diverse responses to extracellular stimuli. The inevitable tradeoff of this plasticity is spontaneous receptor activation and spurious signaling. We show that a ligand-mediated switch in EGFR trafficking enables suppression of spontaneous activation while maintaining EGFR’s capacity to transduce extracellular signals. Autocatalytic phosphorylation of tyrosine 845 on unliganded EGFR monomers is suppressed by vesicular recycling through perinuclear areas with high PTP1B activity. Ligand-binding results in phosphorylation of the c-Cbl docking tyrosine and ubiquitination of the receptor. This secondary signal relies on EGF-induced EGFR self-association and switches suppressive recycling to directional trafficking. The re-routing regulates EGFR signaling response by the transit-time to late endosomes where it is switched-off by high PTP1B activity. This ubiquitin-mediated switch in EGFR trafficking is a uniquely suited solution to suppress spontaneous activation while maintaining responsiveness to EGF.DOI: http://dx.doi.org/10.7554/eLife.12223.001

Graded responses to cell–cell repulsion signals mediated by Ephrin–Eph receptor interactions are specified by EphB2 cluster composition, such that the relative abundance of inactive dimers and active higher-order clusters determines the strength of the repulsive response.

Novel imaging strategies reveal a conformational shift in a receptor tyrosine kinase domain that controls ligand shedding by an ADAM metalloprotease.