INVESTIGADORES
VENTURA Alejandra Cristina
artículos
Título:
A hidden feedback in signaling cascades is revealed
Autor/es:
ALEJANDRA C VENTURA; JACQUES-A. SEPULCHRE; SOFIA D MERAJVER
Revista:
PLoS Computational Biology
Editorial:
Public Library of Science (PLoS)
Referencias:
Año: 2008 vol. 21 p. 1 - 14
ISSN:
1553-734X
Resumen:
Cycles involving covalent modification of proteins are key components
of the intracellular signaling machinery. Each cycle is comprised of
two interconvertable forms of a particular protein. A classic signaling
pathway is structured by a chain or cascade of basic cycle units in
such a way that the activated protein in one cycle promotes the
activation of the next protein in the chain, and so on. Starting from a
mechanistic kinetic description and using a careful perturbation
analysis, we have derived, to our knowledge for the first time, a
consistent approximation of the chain with one variable per cycle. The
model we derive is distinct from the one that has been in use in the
literature for several years, which is a phenomenological extension of
the Goldbeter-Koshland biochemical switch. Even though much has been
done regarding the mathematical modeling of these systems, our
contribution fills a gap between existing models and, in doing so, we
have unveiled critical new properties of this type of signaling
cascades. A key feature of our new model is that a negative feedback
emerges naturally, exerted between each cycle and its predecessor. Due
to this negative feedback, the system displays damped temporal
oscillations under constant stimulation and, most important, propagates
perturbations both forwards and backwards. This last attribute
challenges the widespread notion of unidirectionality in signaling
cascades. Concrete examples of applications to MAPK cascades are
discussed. All these properties are shared by the complete mechanistic
description and our simplified model, but not by previously derived
phenomenological models of signaling cascades.