Systematic quantification of negative feedback mechanisms in the extracellular signal-regulated kinase (ERK) signaling network.
J Biol Chem
; 285(47): 36736-44, 2010 Nov 19.
Article
em En
| MEDLINE
| ID: mdl-20847054
ABSTRACT
Cell responses are actuated by tightly controlled signal transduction pathways. Although the concept of an integrated signaling network replete with interpathway cross-talk and feedback regulation is broadly appreciated, kinetic data of the type needed to characterize such interactions in conjunction with mathematical models are lacking. In mammalian cells, the Ras/ERK pathway controls cell proliferation and other responses stimulated by growth factors, and several cross-talk and feedback mechanisms affecting its activation have been identified. In this work, we take a systematic approach to parse the magnitudes of multiple regulatory mechanisms that attenuate ERK activation through canonical (Ras-dependent) and non-canonical (PI3K-dependent) pathways. In addition to regulation of receptor and ligand levels, we consider three layers of ERK-dependent feedback desensitization of Ras activation, negative regulation of MEK kinase (e.g. Raf) activities, and up-regulation of dual-specificity ERK phosphatases. Our results establish the second of these as the dominant mode of ERK self-regulation in mouse fibroblasts. We further demonstrate that kinetic models of signaling networks, trained on a sufficient diversity of quantitative data, can be reasonably comprehensive, accurate, and predictive in the dynamical sense.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas ras
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Proteínas Quinases Ativadas por Mitógeno
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Retroalimentação Fisiológica
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MAP Quinases Reguladas por Sinal Extracelular
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article