Venkatraman2011 - PLS-UPA behaviour in the presence of substrate competition_1_1_1_1

Venkatraman2011 - PLS-UPA behaviour in the
presence of substrate competition

The posibility of ultrasensitivity and bistable activation of
PLS (Plasmin) and UPA (Urokinase-type plasminogen activator) in
the presence of substrate competition is explained here using a
mathematical model. 

This model is described in the article:

Steady states and dynamics
of urokinase-mediated plasmin activation in silico and in
vitro.

Venkatraman L, Li H, Dewey CF Jr,
White JK, Bhowmick SS, Yu H, Tucker-Kellogg L.
Biophys. J. 2011 Oct; 101(8):
1825-1834
Abstract:

Plasmin (PLS) and urokinase-type plasminogen activator (UPA)
are ubiquitous proteases that regulate the extracellular
environment. Although they are secreted in inactive forms, they
can activate each other through proteolytic cleavage. This
mutual interplay creates the potential for complex dynamics,
which we investigated using mathematical modeling and in vitro
experiments. We constructed ordinary differential equations to
model the conversion of precursor plasminogen into active PLS,
and precursor urokinase (scUPA) into active urokinase (tcUPA).
Although neither PLS nor UPA exhibits allosteric cooperativity,
modeling showed that cooperativity occurred at the system level
because of substrate competition. Computational simulations and
bifurcation analysis predicted that the system would be
bistable over a range of parameters for cooperativity and
positive feedback. Cell-free experiments with recombinant
proteins tested key predictions of the model. PLS activation in
response to scUPA stimulus was found to be cooperative in
vitro. Finally, bistability was demonstrated in vitro by the
presence of two significantly different steady-state levels of
PLS activation for the same levels of stimulus. We conclude
that ultrasensitive, bistable activation of UPA-PLS is possible
in the presence of substrate competition. An ultrasensitive
threshold for activation of PLS and UPA would have
ramifications for normal and disease processes, including
angiogenesis, metastasis, wound healing, and fibrosis.

The cooperativity parameter "ci" was missing in the original
model. The parameter "ci" has been added to the added.

This model is hosted on
BioModels Database
and identified by:
BIOMD0000000630.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.

To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.