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

Cell Systems
Angel StanoevPhilippe I Bastiaens

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.

Citations

Feb 25, 2020·Molecular Systems Biology·Angel StanoevAneta Koseska
Sep 12, 2020·Biochemical Society Transactions·Harrison M YorkSenthil Arumugam
Sep 23, 2018·Nature Communications·Martin BaumdickPhilippe I H Bastiaens
Aug 21, 2020·Science Signaling·Anatoly KiyatkinMark A Lemmon
Mar 30, 2020·Scientific Reports·Debora TenenbaumAlejandra C Ventura
Jul 22, 2020·Annual Review of Cell and Developmental Biology·Aneta Koseska, Philippe I H Bastiaens
Oct 13, 2020·The Biochemical Journal·Stephen C ArtimMark A Lemmon
Oct 31, 2020·The Journal of Biological Chemistry·Kelly KarlKalina Hristova
Jan 18, 2021·The Journal of Biological Chemistry·Kelly KarlKalina Hristova
Mar 12, 2021·Frontiers in Immunology·Ya-Nan WangDongjiao Zhang
Jul 1, 2020·Trends in Molecular Medicine·Dirk Schmidt-Arras, Frank-D Böhmer
Feb 20, 2021·Annual Review of Biochemistry·Mark von Zastrow, Alexander Sorkin

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Methods Mentioned

BETA
two-hybrid
FRET
transfection
PCR
Tandem Repeat
Electrophoresis
FCS
Infrared Imaging
pull down
Confocal microscopy

Software Mentioned

LabVIEW
OpenCV
Igor Pro
R Statistical Software
XPPAUT
CellProfiler
Sepia II
PicoQuant
SymPhoTime
CellR

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