Cell Type–Specific Importance of Ras–c-Raf Complex Association Rate Constants for MAPK Signaling

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Science Signaling  28 Jul 2009:
Vol. 2, Issue 81, pp. ra38
DOI: 10.1126/scisignal.2000397

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Network Topology Dictates Robustness to Dynamical Changes

Stimulation of the epidermal growth factor receptor (EGFR) leads to activation of a large complex signaling network that regulates numerous cellular functions, including cell proliferation, differentiation, and apoptosis. Activation of the kinase c-Raf by the small GTPase Ras is central to the subsequent activation of the extracellular signal–regulated kinase (ERK) mitogen-activated protein kinase (MAPK) branch of the EGFR signaling network. Here, Kiel and Serrano, who previously found that the rate of association between Ras and c-Raf is evolutionarily conserved, investigated the effects of various c-Raf mutations that affected the rate of Ras–c-Raf association, dissociation, or both. They found that association rates seemed to have more effect on ERK signaling than dissociation rates. Intriguingly, however, the effects depended on the specific details of the ERK pathway. In a cell line in which EGF elicits sustained ERK phosphorylation and signaling, c-Raf mutants with similar affinity for Ras, but lower association rates, were less effective at stimulating downstream ERK signaling than wild-type c-Raf, whereas the reverse was true for mutants with higher association rates. In contrast, these effects were not apparent in cell lines in which negative feedback from ERK led to its transient phosphorylation and downstream signaling.