%0 Journal Article
%A Stanoev, Angel
%A Mhamane, Amit
%A Schuermann, Klaus C
%A Grecco, Hernán E
%A Stallaert, Wayne
%A Baumdick, Martin
%A Brüggemann, Yannick
%A Joshi, Maitreyi S
%A Roda-Navarro, Pedro
%A Fengler, Sven
%A Stockert, Rabea
%A Roßmannek, Lisaweta
%A Luig, Jutta
%A Koseska, Aneta
%A Bastiaens, Philippe I H
%T Interdependence between EGFR and Phosphatases Spatially Established by Vesicular Dynamics Generates a Growth Factor Sensing and Responding Network.
%J Cell systems
%V 7
%N 3
%@ 2405-4712
%C Maryland Heights, MO
%I Elsevier
%M DZNE-2020-06557
%P 295-309.e11
%D 2018
%X 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.
%K Cell Membrane: metabolism
%K Computational Biology
%K Cytoplasmic Vesicles: metabolism
%K Endoplasmic Reticulum: metabolism
%K Epidermal Growth Factor: metabolism
%K ErbB Receptors: metabolism
%K Feedback, Physiological
%K Humans
%K MCF-7 Cells
%K Microscopy, Confocal
%K Models, Theoretical
%K Phosphorylation
%K Protein Interaction Maps
%K Protein Transport
%K Protein Tyrosine Phosphatase, Non-Receptor Type 2: metabolism
%K RNA, Small Interfering: genetics
%K Reactive Oxygen Species: metabolism
%K Receptor-Like Protein Tyrosine Phosphatases, Class 5: genetics
%K Receptor-Like Protein Tyrosine Phosphatases, Class 5: metabolism
%K Signal Transduction
%K Single-Cell Analysis
%K RNA, Small Interfering (NLM Chemicals)
%K Reactive Oxygen Species (NLM Chemicals)
%K Epidermal Growth Factor (NLM Chemicals)
%K EGFR protein, human (NLM Chemicals)
%K ErbB Receptors (NLM Chemicals)
%K PTPN2 protein, human (NLM Chemicals)
%K Protein Tyrosine Phosphatase, Non-Receptor Type 2 (NLM Chemicals)
%K Receptor-Like Protein Tyrosine Phosphatases, Class 5 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30145116
%2 pmc:PMC6167251
%R 10.1016/j.cels.2018.06.006
%U https://pub.dzne.de/record/140235