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| Signal transduction: Erk gives feedback
Researchers have used a new tool to dissect the divergent effects of neuronal and epidermal growth factor on the function of the Raf–Mek–Erk mitogen-activated protein kinase (MAPK) pathway. Over the last decade, our understanding of signaling pathways has evolved from delineating largely linear and isolated pathways to an appreciation that signaling molecules are interconnected by tangled webs of negative and positive feedback loops that permit a single component to govern multiple nuanced responses. In Nature Cell Biology, Bastiaens and colleagues use modular response analysis (MRA) to dissect the divergent effects of neuronal and epidermal growth factor (NGF and EGF, respectively) on the function of the Raf–Mek–Erk MAPK pathway.
NGF and EGF both activate the Raf MAPK pathway; however, it has long been appreciated that NGF stimulation causes persistent activation of Erk and differentiation, whereas EGF stimulation results in a transient activation of Erk and proliferation. To understand how Erk activation achieves two distinct downstream responses, the authors used MRA — a technique that measures the changes in steady-state conditions across an entire network when a single pathway component is perturbed, and ultimately generates a network map. As expected, MRA detected a positive linear pathway from Raf-1 via Mek to Erk in both EGF-and NGF-stimulated cells. However, EGF stimulation resulted in negative feedback between Erk and Raf-1 — hence the transient activation of Erk seen under these conditions. This negative feedback likely resulted from promoting Erk-mediated downregulation of the Ras guanine nucleotide exchange factor (GEF) SOS. Conversely, NGF promoted positive feedback between Raf-1 and Mek, causing sustained Erk activation and a prolonged response to stimuli. When examining the kinetics of Erk activation, the authors found that increasing EGF levels led to a gradual increase in Erk phosphorylation. Increasing NGF levels led to an all-or-nothing Erk response, with no intermediate phenotype. Furthermore, terminating NGF signaling after maximal activation of Erk did not result in a dissipation of ERK activity, indicating that NGF stimulation causes Erk to function as a bistable switch. Therefore, the Erk–Raf feedback loop functions as a critical node in determining the nature of the divergent response to stimuli. Positive feedback promotes sustained activation of Erk and cellular differentiation, while negative feedback results in transient activation of Erk, which promotes proliferation. Armed with the understanding of how positive or negative feedback in the Raf MAPK pathway affects cellular response, the authors were able to block specific parts of the pathway to change the cellular response in a predictable manner. For example, protein kinase C (PKC) usually induces positive feedback. Blocking PKC in NGF-stimulated cells resulted in transient, rather than persistent Erk activation. Conversely, activation of PKC in EGF-stimulated cells resulted in sustained Erk signaling, and promoted differentiation. The authors conclude that EGF or NGF stimulation results in divergent activation of a common downstream protein (PKC). Depending on context, PKC can then activate Erk to achieve different cellular responses. The exciting observations made with this first experimental application of MRA hint at its enormous potential for untangling signaling networks. Emily J. Chenette References
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