Abstract
SummaryThe 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.
Highlights
Cells use cell surface receptors such as epidermal growth factor receptor (EGFR) to sense the presence of extracellular growth factors and to interpret the complex dynamic growth factor patterns that can lead to diverse, functionally opposed cellular responses including proliferation, survival, apoptosis, differentiation, and migration (Yarden and Sliwkowski, 2001)
Ligandless and Liganded EGFR Exhibit Distinct Vesicular and Phosphorylation Dynamics To investigate how protein tyrosine phosphatases (PTPs) determine EGFR’s response to growth factors, we first assessed how the phosphorylation of EGFR relates to EGF dose and its vesicular trafficking
Tagged EGFR-mTFP was ectopically expressed in breast cancer-derived MCF7 cells with low endogenous EGFR expression ($103/cell [Charafe-Jauffret et al, 2005], Figure S1A), to a level that fell within the endogenous EGFR expression range of the related MCF10A cells
Summary
Cells use cell surface receptors such as epidermal growth factor receptor (EGFR) to sense the presence of extracellular growth factors and to interpret the complex dynamic growth factor patterns that can lead to diverse, functionally opposed cellular responses including proliferation, survival, apoptosis, differentiation, and migration (Yarden and Sliwkowski, 2001). Collective EGFR phosphorylation dynamics is thereby the first layer that translates the information encoded in time-varying extracellular growth factor patterns into a cellular outcome. Such a system must have two essential characteristics: sensitivity to non-stationary growth factor inputs and capability to transform these inputs into an intracellular activity pattern that varies in both space and time. How this is accomplished on the molecular level remains unclear. Even though large-scale studies based on enzymatic assays of purified PTPs (Barr et al, 2009), membrane two-hybrid assays (Yao et al, 2017), and biochemical assays on cell extracts after small interfering RNA (siRNA) knockdown (Tarcic et al, 2009) have identified a number of PTPs that dephosphorylate EGFR (Liu and Chernoff, 1997; Tiganis et al, 1998; Yuan et al, 2010), the dominant PTPs that act in concert with EGFR to determine its collective phosphorylation dynamics remain unknown
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