Vesicular dynamics resolve the competition between chemoattraction and contact inhibition in the control of cellular migration
Wayne Stallaert1, Ola Sabet1, Lisa Baak1, Dominik Jung1 and Philippe I. Bastiaens1,2
1Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Str.11, 44227 Dortmund, Germany; 2Faculty of Chemistry and Chemical Biology, TU Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund, Germany
The control of cellular migration is governed by a mutually opposed relationship between the pro-migratory epidermal growth factor receptor (EGFR) and the EphA2 receptor, a mediator of contact inhibition of locomotion. Using a combination of flow cytometry and single live cell imaging, we demonstrate that a recursive relationship between receptor tyrosine kinase (RTK) signaling and vesicular trafficking controls the decision to migrate at the level of the individual cell. Through the activation of Akt, EGFR increases vesicular trafficking to the plasma membrane, potentiating its own activity at the leading edge and promoting the transition to a migratory state. This spatial positive feedback is engaged heterogeneously within the population, with the proportion of cells induced to migrate increasing with EGF concentration. EGF-promoted migration is directly opposed by EphA2 activation through the inhibition of Akt and the suppression of vesicular recycling. By decreasing the plasma membrane activity of EGFR, the amount of ephrinA1-EphA2 interaction determines the proportion of cells initiating a migratory response to EGF. The reciprocal relationship between cellular signaling and vesicular trafficking, therefore, provides a mechanism through which cells can interpret a complex and changing extracellular environment and influence the response to stimuli in a context-dependent manner.