Journal Article

DZNE-2020-06557

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Interdependence between EGFR and Phosphatases Spatially Established by Vesicular Dynamics Generates a Growth Factor Sensing and Responding Network.

Stanoev, A. ; Mhamane, A. ; Schuermann, K. C. ; Grecco, H. E. ; Stallaert, W. ; Baumdick, M. ; Brüggemann, Y. ; Joshi, M. S. ; Roda-Navarro, P. ; Fengler, S.DZNE* ; Stockert, R. ; Roßmannek, L. ; Luig, J. ; Koseska, A. ; Bastiaens, P. I. H. (Corresponding author)

2018
Elsevier Maryland Heights, MO

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Please use a persistent id in citations: doi:10.1016/j.cels.2018.06.006

Abstract: 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.

Keyword(s): Cell Membrane: metabolism (MeSH) ; Computational Biology (MeSH) ; Cytoplasmic Vesicles: metabolism (MeSH) ; Endoplasmic Reticulum: metabolism (MeSH) ; Epidermal Growth Factor: metabolism (MeSH) ; ErbB Receptors: metabolism (MeSH) ; Feedback, Physiological (MeSH) ; Humans (MeSH) ; MCF-7 Cells (MeSH) ; Microscopy, Confocal (MeSH) ; Models, Theoretical (MeSH) ; Phosphorylation (MeSH) ; Protein Interaction Maps (MeSH) ; Protein Transport (MeSH) ; Protein Tyrosine Phosphatase, Non-Receptor Type 2: metabolism (MeSH) ; RNA, Small Interfering: genetics (MeSH) ; Reactive Oxygen Species: metabolism (MeSH) ; Receptor-Like Protein Tyrosine Phosphatases, Class 5: genetics (MeSH) ; Receptor-Like Protein Tyrosine Phosphatases, Class 5: metabolism (MeSH) ; Signal Transduction (MeSH) ; Single-Cell Analysis (MeSH) ; RNA, Small Interfering ; Reactive Oxygen Species ; Epidermal Growth Factor ; EGFR protein, human ; ErbB Receptors ; PTPN2 protein, human ; Protein Tyrosine Phosphatase, Non-Receptor Type 2 ; Receptor-Like Protein Tyrosine Phosphatases, Class 5

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Contributing Institute(s):

1. Systems Phenomics (AG Fava 1)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2018

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Database coverage:
; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; IF >= 10 ; JCR ; SCOPUS ; Web of Science Core Collection

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