Ortega2006 - bistability from double phosphorylation in signal transduction

Ortega2006 - bistability from double
phosphorylation in signal transduction

This model is described in the article:

Bistability from double
phosphorylation in signal transduction. Kinetic and structural
requirements.

Ortega F, Garcés JL, Mas F,
Kholodenko BN, Cascante M.
FEBS J. 2006 Sep; 273(17):
3915-3926
Abstract:

Previous studies have suggested that positive feedback loops
and ultrasensitivity are prerequisites for bistability in
covalent modification cascades. However, it was recently shown
that bistability and hysteresis can also arise solely from
multisite phosphorylation. Here we analytically demonstrate
that double phosphorylation of a protein (or other covalent
modification) generates bistability only if: (a) the two
phosphorylation (or the two dephosphorylation) reactions are
catalyzed by the same enzyme; (b) the kinetics operate at least
partly in the zero-order region; and (c) the ratio of the
catalytic constants of the phosphorylation and
dephosphorylation steps in the first modification cycle is less
than this ratio in the second cycle. We also show that
multisite phosphorylation enlarges the region of kinetic
parameter values in which bistability appears, but does not
generate multistability. In addition, we conclude that a
cascade of phosphorylation/dephosphorylation cycles generates
multiple steady states in the absence of feedback or
feedforward loops. Our results show that bistable behavior in
covalent modification cascades relies not only on the structure
and regulatory pattern of feedback/feedforward loops, but also
on the kinetic characteristics of their component proteins.

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