TY  - JOUR
AU  - Stanoev, Angel
AU  - Mhamane, Amit
AU  - Schuermann, Klaus C
AU  - Grecco, Hernán E
AU  - Stallaert, Wayne
AU  - Baumdick, Martin
AU  - Brüggemann, Yannick
AU  - Joshi, Maitreyi S
AU  - Roda-Navarro, Pedro
AU  - Fengler, Sven
AU  - Stockert, Rabea
AU  - Roßmannek, Lisaweta
AU  - Luig, Jutta
AU  - Koseska, Aneta
AU  - Bastiaens, Philippe I H
TI  - Interdependence between EGFR and Phosphatases Spatially Established by Vesicular Dynamics Generates a Growth Factor Sensing and Responding Network.
JO  - Cell systems
VL  - 7
IS  - 3
SN  - 2405-4712
CY  - Maryland Heights, MO
PB  - Elsevier
M1  - DZNE-2020-06557
SP  - 295-309.e11
PY  - 2018
AB  - 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.
KW  - Cell Membrane: metabolism
KW  - Computational Biology
KW  - Cytoplasmic Vesicles: metabolism
KW  - Endoplasmic Reticulum: metabolism
KW  - Epidermal Growth Factor: metabolism
KW  - ErbB Receptors: metabolism
KW  - Feedback, Physiological
KW  - Humans
KW  - MCF-7 Cells
KW  - Microscopy, Confocal
KW  - Models, Theoretical
KW  - Phosphorylation
KW  - Protein Interaction Maps
KW  - Protein Transport
KW  - Protein Tyrosine Phosphatase, Non-Receptor Type 2: metabolism
KW  - RNA, Small Interfering: genetics
KW  - Reactive Oxygen Species: metabolism
KW  - Receptor-Like Protein Tyrosine Phosphatases, Class 5: genetics
KW  - Receptor-Like Protein Tyrosine Phosphatases, Class 5: metabolism
KW  - Signal Transduction
KW  - Single-Cell Analysis
KW  - RNA, Small Interfering (NLM Chemicals)
KW  - Reactive Oxygen Species (NLM Chemicals)
KW  - Epidermal Growth Factor (NLM Chemicals)
KW  - EGFR protein, human (NLM Chemicals)
KW  - ErbB Receptors (NLM Chemicals)
KW  - PTPN2 protein, human (NLM Chemicals)
KW  - Protein Tyrosine Phosphatase, Non-Receptor Type 2 (NLM Chemicals)
KW  - Receptor-Like Protein Tyrosine Phosphatases, Class 5 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30145116
C2  - pmc:PMC6167251
DO  - DOI:10.1016/j.cels.2018.06.006
UR  - https://pub.dzne.de/record/140235
ER  -