Figure 5.
Dynamics of the Spatially Distributed EGFR-PTP Network
(A) Scheme of the EGFR-PTP interaction network established through EGFR trafficking dynamics. EGFR interacts with PTPRG/PTPRJ at the PM and PTPN2 in the cytoplasm. All notations as in Figure 1L.
(B) Causality diagram that corresponds to (A). Red/blue lines: causal interactions; green arrow: ligand binding.
(C) 3D-bifurcation diagram for double-negative EGFR-PTPRG feedback network topology at the plasma membrane, showing the dependence of monomeric EGFR phosphorylation (EGFRp) on PTPRG/EGFR expression ratio and fraction of liganded receptors. Forward (green) and backward (red) dose-response trajectories are shown for PTPRG/EGFR = 1.9, with corresponding orthographic projections on the right profile plane.
(D) 3D-bifurcation diagram as in (C), for the combined toggle-switch/negative regulation/negative-feedback network topology established by ligandless EGFR vesicular recycling. Projections are the same as in (C).
(E) Simulated temporal profiles of the fractions of liganded (dark) and phosphorylated receptors (light) in response to a train of pulses (gray), when the system is organized in the bistable regime (left), close to the bistability region (middle), and in the monostable regime (right) for the complete EGFR/PTP network as in (D).
(F) Temporal traces of the fraction of ligand-bound (EGF-Alexa647/EGFR-mCitrine, dark color) and phosphorylated EGFR estimated by PTB-mCherry translocation to the plasma membrane (PTB-mCherry/EGFR-mCitrine, light color) in live MCF7 cells expressing non-targeting siRNA (middle, n = 4, N = 1), following siRNA-mediated knockdown of PTPRG (left, n = 5, N = 2), and ectopic Rab11S25N expression (right, n = 16, N = 2). Data were acquired at 1-min intervals following 20 ng/mL 5P-EGF every 30 min. Means ± SD are shown. Lower boxes depict the normalized differences between the fraction of phosphorylated and liganded EGFR.