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|Title:||Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1||Authors:||Venkatraman, Lakshmi
White, Jacob K.
Bhowmick, Sourav S.
So, Peter T.
Narmada, Balakrishnan Chakrapani
Dewey Jr., C. Forbes
|Keywords:||DRNTU::Engineering::Computer science and engineering||Issue Date:||2012||Source:||Venkatraman, 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.||Series/Report no.:||Biophysical journal||Abstract:||Transforming 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.||URI:||https://hdl.handle.net/10356/98087
|ISSN:||0006-3495||DOI:||http://dx.doi.org/10.1016/j.bpj.2012.06.050||Rights:||© 2012 Biophysical Society.||Fulltext Permission:||none||Fulltext Availability:||No Fulltext|
|Appears in Collections:||SCSE Journal Articles|
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