Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/98087
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dc.contributor.authorVenkatraman, Lakshmien
dc.contributor.authorChia, Ser-Mienen
dc.contributor.authorWhite, Jacob K.en
dc.contributor.authorBhowmick, Sourav S.en
dc.contributor.authorSo, Peter T.en
dc.contributor.authorNarmada, Balakrishnan Chakrapanien
dc.contributor.authorDewey Jr., C. Forbesen
dc.contributor.authorTucker-Kellogg, Lisaen
dc.contributor.authorYu, Hanryen
dc.date.accessioned2013-06-27T03:48:51Zen
dc.date.accessioned2019-12-06T19:50:25Z-
dc.date.available2013-06-27T03:48:51Zen
dc.date.available2019-12-06T19:50:25Z-
dc.date.copyright2012en
dc.date.issued2012en
dc.identifier.citationVenkatraman, L., Chia, S.-M., Narmada, B. C., White, J. K., Bhowmick, S. S., Dewey Jr., C. F., et al. (2012). Plasmin Triggers a Switch-Like Decrease in Thrombospondin-Dependent Activation of TGF-β1. Biophysical Journal, 103(5), 1060-1068.en
dc.identifier.issn0006-3495en
dc.identifier.urihttps://hdl.handle.net/10356/98087-
dc.identifier.urihttp://hdl.handle.net/10220/10784en
dc.description.abstractTransforming growth factor-β1 (TGF-β1) is a potent regulator of extracellular matrix production, wound healing, differentiation, and immune response, and is implicated in the progression of fibrotic diseases and cancer. Extracellular activation of TGF-β1 from its latent form provides spatiotemporal control over TGF-β1 signaling, but the current understanding of TGF-β1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individually as activators of TGF-β1, and in this work we used a systems-level approach with mathematical modeling and in vitro experiments to study the interplay between PLS and TSP1 in TGF-β1 activation. Simulations and steady-state analysis predicted a switch-like bistable transition between two levels of active TGF-β1, with an inverse correlation between PLS and TSP1. In particular, the model predicted that increasing PLS breaks a TSP1-TGF-β1 positive feedback loop and causes an unexpected net decrease in TGF-β1 activation. To test these predictions in vitro, we treated rat hepatocytes and hepatic stellate cells with PLS, which caused proteolytic cleavage of TSP1 and decreased activation of TGF-β1. The TGF-β1 activation levels showed a cooperative dose response, and a test of hysteresis in the cocultured cells validated that TGF-β1 activation is bistable. We conclude that switch-like behavior arises from natural competition between two distinct modes of TGF-β1 activation: a TSP1-mediated mode of high activation and a PLS-mediated mode of low activation. This switch suggests an explanation for the unexpected effects of the plasminogen activation system on TGF-β1 in fibrotic diseases in vivo, as well as novel prognostic and therapeutic approaches for diseases with TGF-β dysregulation.en
dc.language.isoenen
dc.relation.ispartofseriesBiophysical journalen
dc.rights© 2012 Biophysical Society.en
dc.subjectDRNTU::Engineering::Computer science and engineeringen
dc.titlePlasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1en
dc.typeJournal Articleen
dc.contributor.schoolSchool of Computer Engineeringen
dc.contributor.researchSingapore-MIT Alliance, Computational Systems Biology Programmeen
dc.identifier.doihttp://dx.doi.org/10.1016/j.bpj.2012.06.050en
item.grantfulltextnone-
item.fulltextNo Fulltext-
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