Abstract
We formulated a computational model for a MAPK signaling cascade downstream of the EGF receptor to investigate how interlinked positive and negative feedback loops process EGF signals into ERK pulses of constant amplitude but dose-dependent duration and frequency. A positive feedback loop involving RAS and SOS, which leads to bistability and allows for switch-like responses to inputs, is nested within a negative feedback loop that encompasses RAS and RAF, MEK, and ERK that inhibits SOS via phosphorylation. This negative feedback, operating on a longer time scale, changes switch-like behavior into oscillations having a period of 1 hour or longer. Two auxiliary negative feedback loops, from ERK to MEK and RAF, placed downstream of the positive feedback, shape the temporal ERK activity profile but are dispensable for oscillations. Thus, the positive feedback introduces a hierarchy among negative feedback loops, such that the effect of a negative feedback depends on its position with respect to the positive feedback loop. Furthermore, a combination of the fast positive feedback involving slow-diffusing membrane components with slower negative feedbacks involving faster diffusing cytoplasmic components leads to local excitation/global inhibition dynamics, which allows the MAPK cascade to transmit paracrine EGF signals into spatially non-uniform ERK activity pulses.
Highlights
A canonical mitogen-activated protein kinase (MAPK) pathway responsible for transducing signals from growth factors consists of three tiers of sequentially activated protein kinases: RAF, MEK, and ERK1
We construct a computational model for MAPK/ERK signaling downstream of EGFR with three aims: (i) to verify whether the combination of the positive and negative feedbacks considered in the model leads to observed relaxation oscillations, (ii) to characterize the functional roles of the different feedback loops depending on their position in the network, and (iii) to analyze the consequences of proteins participating in the feedback loops being localized to distinct subcellular compartments for spatiotemporal profiles of the response
Our model was built and analyzed to determine whether positive feedback between plasma membrane-associated signaling proteins could potentially be responsible for the observed behavior, which includes apparent relaxation oscillations in ERK activity
Summary
A canonical mitogen-activated protein kinase (MAPK) pathway responsible for transducing signals from growth factors consists of three tiers of sequentially activated protein kinases: RAF, MEK, and ERK1. System-level mechanisms of controlling information processing in MAPK are still not fully understood, partially due to the fact that systems involving interlocked positive and negative feedback loops may exhibit rich nonlinear dynamical behavior Dynamics assumed by such complex systems depends on the characteristic time scales involved and network connectivity/topology, i.e., where the feedbacks act and how they relate to each other. In recent work[30], we observed similar pulses using a sensor based on phosphorylation-regulated Förster resonance energy transfer (FRET) to monitor EGF-stimulated ERK activity in single MCF10A cells These pulses differ from constant-frequency quasisinusoidal oscillations in ERK nuclear translocation observed in other studies[26] and are characterized by an EGF dose-independent amplitude and an EGF dose-dependent period. The proposed model is corroborated by experimental analysis of single-cell responses to a broad range of EGF doses using a fast sensor of ERK activity based on phosphorylation-dependent regulation of nucleocytoplasmic shuttling[31,32]
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