Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.bpj.2011.08.054
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dc.titleSteady states and dynamics of urokinase-mediated plasmin activation in silico and in vitro
dc.contributor.authorVenkatraman, L.
dc.contributor.authorLi, H.
dc.contributor.authorDewey Jr., C.F.
dc.contributor.authorWhite, J.K.
dc.contributor.authorBhowmick, S.S.
dc.contributor.authorYu, H.
dc.contributor.authorTucker-Kellogg, L.
dc.date.accessioned2014-12-12T07:51:54Z
dc.date.available2014-12-12T07:51:54Z
dc.date.issued2011-10-19
dc.identifier.citationVenkatraman, L., Li, H., Dewey Jr., C.F., White, J.K., Bhowmick, S.S., Yu, H., Tucker-Kellogg, L. (2011-10-19). Steady states and dynamics of urokinase-mediated plasmin activation in silico and in vitro. Biophysical Journal 101 (8) : 1825-1834. ScholarBank@NUS Repository. https://doi.org/10.1016/j.bpj.2011.08.054
dc.identifier.issn00063495
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/116603
dc.description.abstractPlasmin (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. © 2011 Biophysical Society.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1016/j.bpj.2011.08.054
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentMECHANOBIOLOGY INSTITUTE
dc.contributor.departmentNATIONAL UNIVERSITY MEDICAL INSTITUTES
dc.description.doi10.1016/j.bpj.2011.08.054
dc.description.sourcetitleBiophysical Journal
dc.description.volume101
dc.description.issue8
dc.description.page1825-1834
dc.description.codenBIOJA
dc.identifier.isiut000296075800005
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