Long Signaling Cascades Tend to Attenuate Retroactivity

• Autores: Ossareh, Hamid R.; Ventura, Alejandra; Merajver, Sofia D.; Del Vecchio, Domitilla
• Año de publicación: 2011
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Signaling Pathways; Retroactivity; Attenuation
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Signaling pathways consisting of phosphorylation/dephosphorylation cycles with no explicit feedback allow signals to propagate not only from upstream to downstream but also from downstream to upstream due to retroactivity at the interconnection between phosphorylation/dephosphorylation cycles. However, the extent to which a downstream perturbation can propagate upstream in a signaling cascade and the parameters that affect this propagation are presently unknown. Here, we determine the downstream-to-upstream steady-state gain at each stage of the signaling cascade as a function of the cascade parameters. This gain can be made smaller than 1 (attenuation) by sufficiently fast kinase rates compared to the phosphatase rates and/or by sufficiently large Michaelis-Menten constants and sufficiently low amounts of total stage protein. Numerical studies performed on sets of biologically relevant parameters indicated that ∼50% of these parameters could give rise to amplification of the downstream perturbation at some stage in a three-stage cascade. In an n-stage cascade, the percentage of parameters that lead to an overall attenuation from the last stage to the first stage monotonically increases with the cascade length n and reaches 100% for cascades of length at least 6.
Fil: Ossareh, Hamid R.. University of Michigan; Estados Unidos
Fil: Ventura, Alejandra. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; Argentina
Fil: Merajver, Sofia D.. University of Michigan; Estados Unidos
Fil: Del Vecchio, Domitilla. Massachusetts Institute of Technology; Estados Unidos