Vesicular trafficking dynamics enable context-dependent regulation of ErbB receptor activity and signaling

Abstract

The ErbB signaling network comprises a complex dynamic system, which regulates a diverse set of cellular behaviors. In this thesis, we examined how regulating the distribution of ErbB receptors between the plasma membrane and different endosomal compartments enables contextual regulation of receptor activity and signaling. In the first part of this work, we investigated how spatial regulation of EGFR controls its autocatalytic activity. We found that autonomously activated and EGF activated receptors are processed differently by the endocytic machinery. Constitutive vesicular recycling through perinuclear areas with high PTP1B phosphatase activity suppresses autonomous receptor activation in the absence of ligand, while maintaining EGFR abundance at the PM. In contrast, EGF binding enhances EGFR self-association and phosphorylation of the c-Cbl docking tyrosine Y1045, which results in receptor ubiquitination, internalization and lysosomal degradation. The coupling of EGFR self-association state, ubiquitination and vesicular dynamics thereby allows for the coexistence of a continuous safeguard cycle, while maintaining sensitivity to growth factor stimulation.In the second part of this work, we examined how ligand-specific ErbB receptor trafficking determines Erk signaling dynamics and localization. We found that EGF or heregulin (HRG) differentially modulate ErbB receptor trafficking to generate distinct spatiotemporal patterns of receptor activities, leading to the activation of Erk from different subcellular compartments (plasma membrane and endosomes). The subcellular localization of Erk activation influences its interaction with different effector proteins and thereby generates ligand-specific cellular responses. Proliferative Erk signals are transmitted to the nucleus, irrespective of their spatial origin, while the Erk dependent phosphorylation of pro-migratory effectors relies on membrane proximal Erk activity. Collectively our findings highlight how vesicular dynamics enable context dependent spatial regulation of ErbB activity and downstream signaling events.