title: Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.
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.
authors.affiliation: Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Venkatraman
authors.forename: Ser-Mien
authors.initials: SM
authors.lastname: Chia
authors.forename: Balakrishnan Chakrapani
authors.initials: BC
authors.lastname: Narmada
authors.forename: Jacob K
authors.initials: JK
authors.lastname: White
authors.forename: Sourav S
authors.initials: SS
authors.lastname: Bhowmick
authors.forename: C
authors.initials: C
authors.lastname: Forbes Dewey
authors.forename: Peter T
authors.initials: PT
authors.lastname: So
authors.forename: Lisa
authors.initials: L
authors.lastname: Tucker-Kellogg
authors.forename: Hanry
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005341:Fibrinolysin / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D055550:Protein Stability; D051381:Rats; D019700:Thrombospondin 1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; D005341:Fibrinolysin