Biology subjects

Stallaert, W.

Publications and source records attributed to Stallaert, W..

2 recordsLinked to original sources

bioRxiv2018

Interdependence of EGFR with PTPs on juxtaposed membranes generates a growth factor sensing and responding network

The proto-oncogenic epidermal growth factor receptor (EGFR) is a tyrosine kinase whose sensitivity to growth factors (GFs) and signal duration determines cellular behavior. We resolve how EGFRs response to epidermal growth factor (EGF) originates from dynamically established recursive interactions with spatially organized protein tyrosine phosphatases (PTPs). Opposed genetic PTP perturbations enabled identification of receptor-like PTPRG/J at the plasma membrane (PM) and endoplasmic reticulum (ER) associated PTPN2 as the major EGFR dephosphorylating activities. Imaging spatial-temporal PTP reactivity then revealed that vesicular trafficking establishes a spatially-distributed negative feedback with PTPN2 that determines signal duration, whereas single cell dose-response analysis uncovered a ROS-mediated toggle switch between autocatalytically activated monomeric EGFR and the tumor suppressor PTPRG that governs EGFRs sensitivity to EGF. Vesicular recycling of monomeric EGFR unifies the interactions with these PTPs on juxtaposed membranes, dynamically generating a network architecture that can sense and respond to time varying growth factor signals.

systems biology↗

bioRxiv2017

Contact inhibitory Eph signalling decouples EGFR activity from vesicular recycling to generate contextual plasticity

The ability of cells to adapt their behavior to growth factors in relation to their environment is an essential aspect of tissue development and homeostasis. Here we show that Eph receptor signaling from cell-cell contacts changes the cellular response to EGFR activation by altering its vesicular trafficking. Eph receptor activation traps EGFR in Rab5-positive early endosomes through an inhibition of Akt-dependent vesicular recycling. By altering the spatial distribution of EGFR activity during EGF stimulation, Eph receptor activation selectively suppresses migratory Akt signaling from the plasma membrane, while preserving proliferative ERK signaling from endosomes. We also show that soluble extracellular signals engaging the G-protein coupled receptor Kiss1 similarly suppress vesicular recycling to alter EGFR signaling. The cellular environment can thus modulate EGFR vesicular trafficking dynamics to generate context-dependent responses to EGF stimulation.\n\nSummaryEph receptor activation generates context-dependent cellular responses to EGFR activation by altering its vesicular trafficking dynamics.

cell biology↗