Steady States and Dynamics of Urokinase-Mediated Plasmin Activation In Silico and In Vitro
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Venkatraman-2011-Steady States and Dy.pdf
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Author(s)
Venkatraman, Lakshmi
Li, Huipeng
Dewey, C. Forbes
White, Jacob K.
Bhowmick, Sourav S.
Yu, Hanry
Tucker-Kellogg, Lisa
White, Jacob K.
Date Issued
October 2011
Journal
Biophysical Journal
Publisher
Elsevier
Citation
Venkatraman, Lakshmi, Huipeng Li, C. Forbes Dewey, Jacob K. White, Sourav S. Bhowmick, Hanry Yu, and Lisa Tucker-Kellogg. “Steady States and Dynamics of Urokinase-Mediated Plasmin Activation In Silico and In Vitro.” Biophysical Journal 101, no. 8 (October 2011): 1825–1834. © 2011 Biophysical Society
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Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Massachusetts Institute of Technology. Department of Mechanical Engineering
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DOI of Published Version
https://doi.org/10.1016/j.bpj.2011.08.054
