Interdependence between EGFR and Phosphatases Spatially Established by Vesicular Dynamics Generates a Growth Factor Sensing and Responding Network
| Autor: | Lisaweta Roßmannek, Hernán E. Grecco, Jutta Luig, Philippe I. H. Bastiaens, Rabea Stockert, Amit Mhamane, Pedro Roda-Navarro, Angel Stanoev, Sven Fengler, Klaus C. Schuermann, Wayne Stallaert, Maitreyi S. Joshi, Aneta Koseska, Martin Baumdick, Yannick Brüggemann |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
genetics [Receptor-Like Protein Tyrosine Phosphatases Class 5] IN SITU REACTIVITY OF PHOSPHATASES SPATIAL-TEMPORAL Ciencias Físicas medicine.medical_treatment genetics [RNA Small Interfering] Protein tyrosine phosphatase Endoplasmic Reticulum GROWTH FACTOR SENSING VESICULAR TRAFFICKING metabolism [Cytoplasmic Vesicles] metabolism [Epidermal Growth Factor] law.invention dynamic organization QUANTIFIABLE GENETIC PERTURBATIONS metabolism [Endoplasmic Reticulum] Epidermal growth factor law EGFR phosphatome identification growth factor sensing metabolism [Reactive Oxygen Species] Protein Interaction Maps Epidermal growth factor receptor Phosphorylation RNA Small Interfering functional imaging Feedback Physiological Protein Tyrosine Phosphatase Non-Receptor Type 2 Microscopy Confocal biology Receptor-Like Protein Tyrosine Phosphatases Class 5 Chemistry Cell biology ErbB Receptors Protein Transport AUTOCATALYSIS in situ reactivity of phosphatases MCF-7 Cells Single-Cell Analysis vesicular trafficking Tyrosine kinase CIENCIAS NATURALES Y EXACTAS metabolism [ErbB Receptors] Signal Transduction FUNCTIONAL IMAGING Histology PTPN2 protein human Phosphatase Article metabolism [Cell Membrane] Pathology and Forensic Medicine Ciencias Biológicas 03 medical and health sciences EGFR protein human spatial-temporal Biología Celular Microbiología ddc:570 Negative feedback autocatalysis dynamic systems theory medicine Humans quantifiable genetic perturbations DYNAMIC SYSTEMS THEORY Óptica metabolism [Protein Tyrosine Phosphatase Non-Receptor Type 2] Epidermal Growth Factor Growth factor Cell Membrane Cytoplasmic Vesicles Computational Biology Cell Biology EGFR PHOSPHATOME IDENTIFICATION Models Theoretical metabolism [Receptor-Like Protein Tyrosine Phosphatases Class 5] 030104 developmental biology DYNAMIC ORGANIZATION biology.protein Suppressor Reactive Oxygen Species |
| Zdroj: | Cell systems 7(3), 295-309.e11 (2018). doi:10.1016/j.cels.2018.06.006 Cell Systems |
| ISSN: | 2405-4712 |
| DOI: | 10.1016/j.cels.2018.06.006 |
| Popis: | Summary 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. Graphical Abstract Highlights • Genetic perturbations reveal three membrane PTPs having highest reactivity for EGFR • Vesicular dynamics establishes a spatially distributed EGFR-PTP network • Autocatalytic activation and recursive interactions with PTPs dictate EGFR response • Dynamical operation mode of this network enables time-varying growth factor sensing Cells continuously respond to temporal changes of growth factors, but it is unclear how the surface receptor tyrosine kinase EGFR senses and translates these changes. We identify three protein tyrosine phosphatases localized on the plasma membrane and the ER that together do more than erase the phosphorylation signal written by this receptor. We show that vesicular recycling unifies the recursive interactions of these phosphatases with autocatalytically activated EGFR, thereby enabling responsiveness to time-varying EGF stimuli. |
| Databáze: | OpenAIRE |
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