Please use this identifier to cite or link to this item:
Title: Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1
Authors: Venkatraman, Lakshmi
Chia, Ser-Mien
White, Jacob K.
Bhowmick, Sourav S.
So, Peter T.
Narmada, Balakrishnan Chakrapani
Dewey Jr., C. Forbes
Tucker-Kellogg, Lisa
Yu, Hanry
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.
ISSN: 0006-3495
DOI: 10.1016/j.bpj.2012.06.050
Rights: © 2012 Biophysical Society.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SCSE Journal Articles

Google ScholarTM




Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.