MODEL1303130001
type: SBMLModel
name: Venkatraman2011 - PLS-UPA behaviour in the presence of substrate competition
reaction: COPASI6
species: COPASI2
reaction: COPASI15
reaction: COPASI8
time units: time
reaction: COPASI12
reaction: COPASI5
notes: 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 19;101(8):1825-34. 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, incl…
reaction: COPASI14
is described by: http://identifiers.org/pubmed/22004735
reaction: COPASI16
name: Constant flux (irreversible)
volume units: volume
reaction: COPASI9
reaction: COPASI13
reaction: COPASI3
reaction: COPASI7
curated: false
reaction: COPASI11
length unit: length
reaction: COPASI10
area units: area
reaction: COPASI4

COPASI6
type: Reaction
modifier: MODEL1303130001#
fast: false
reversible: false
name: reaction_4

http://identifiers.org/biomodels.db/MODEL1303130001#_806c65b3_2916_4d25_bead_239128203107
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: 0.0
initial amount: NaN
name: Xpls

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type: Compartment
constant: true
size: 1.0
spatial dimensions: 3.0
name: compartment

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type: Species
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has only substance units: false
initial concentration: 0.2
initial amount: NaN
name: X

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type: Species
constant: false
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initial concentration: 0.0
initial amount: NaN
name: tcupa

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type: Species
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type: Species
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initial concentration: 0.002
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name: scupa

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type: SpeciesReference
stoichiometry: 1.0

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type: Parameter
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value: 40.0
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type: Parameter
constant: true
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COPASI15
type: Reaction
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reversible: false
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type: Parameter
constant: true
value: 0.035
name: keff_zymogen

COPASI8
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modifier: MODEL1303130001#
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reversible: false
name: reaction_6

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type: Parameter
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value: 0.0032
name: alpha1

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type: Parameter
constant: true
value: 1.0
name: ci

COPASI12
type: Reaction
modifier: MODEL1303130001#
fast: false
reversible: false
name: reaction_10

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COPASI5
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modifier: MODEL1303130001#
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reversible: false
name: reaction_3

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type: Parameter
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COPASI14
type: Reaction
fast: false
reversible: false
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COPASI16
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reversible: false
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type: Parameter
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value: 0.01
name: alpha3

COPASI9
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modifier: MODEL1303130001#
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reversible: false
name: reaction_7

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COPASI13
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modifier: MODEL1303130001#
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reversible: false
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name: alpha2

COPASI3
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name: substance

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exponent: 1.0
scale: -6
multipler: 1.0
kind: MOLE

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type: Parameter
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value: 0.9
name: keff_pos

COPASI7
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reversible: false
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COPASI10
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COPASI4
type: Reaction
modifier: MODEL1303130001#
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reversible: false
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