Interdependence between EGFR and Phosphatases Spatially Established by Vesicular Dynamics Generates a Growth Factor Sensing and Responding Network

STANOEV, ANGEL; MHAMANE, AMIT; SCHUERMANN, KLAUS C.; GRECCO, HERNÁN E.; STALLAERT, WAYNE; BAUMDICK, MARTIN; BRÜGGEMANN, YANNICK; JOSHI, MAITREYI S.; RODA-NAVARRO, PEDRO; FENGLER, SVEN; STOCKERT, RABEA; ROßMANNEK, LISAWETA; LUIG, JUTTA; KOSESKA, ANETA; BASTIAENS, PHILIPPE I.H.

Cell Systems

Cell Press

Lugar: Cambridge; Año: 2018

2405-4712

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