Growth factor-dependent ErbB vesicular dynamics couple receptor signaling to spatially and functionally distinct Erk pools

Abstract

Growth factor-dependent vesicular dynamics allow cells to regulate the spatial distribution of growth factor receptors and thereby their coupling to downstream signaling effectors that guide cellular responses. We found that the ErbB ligands epidermal growth factor (EGF) and heregulin (HRG) generated distinct spatiotemporal patterns of cognate receptor activities to activate distinct subcellular pools of the extracellular signal-regulated kinase (Erk). Sustained plasma membrane activity of the receptor tyrosine kinases ErbB2/ErbB3 signaled to Erk complexed with the scaffold protein KSR to promote promigratory EphA2 phosphorylation and cellular motility upon HRG stimulation. In contrast, receptor-saturating EGF stimuli caused proliferation-inducing transient activation of cytoplasmic Erk due to the rapid internalization of EGF receptors (EGFR or ErbB1) toward endosomes. Paradoxically, promigratory signaling mediated by Erk complexed to KSR was sustained at low EGF concentrations by vesicular recycling that maintained steady-state amounts of active, phosphorylated EGFR at the plasma membrane. Thus, the effect of ligand identity and concentration on determining ErbB vesicular dynamics constitutes a mechanism by which cells can transduce growth factor composition through spatially distinct Erk pools to enable functionally diverse cellular responses.