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Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-?1.

ABSTRACT: Transforming growth factor-?1 (TGF-?1) 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-?1 from its latent form provides spatiotemporal control over TGF-?1 signaling, but the current understanding of TGF-?1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individually as activators of TGF-?1, 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-?1 activation. Simulations and steady-state analysis predicted a switch-like bistable transition between two levels of active TGF-?1, with an inverse correlation between PLS and TSP1. In particular, the model predicted that increasing PLS breaks a TSP1-TGF-?1 positive feedback loop and causes an unexpected net decrease in TGF-?1 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-?1. The TGF-?1 activation levels showed a cooperative dose response, and a test of hysteresis in the cocultured cells validated that TGF-?1 activation is bistable. We conclude that switch-like behavior arises from natural competition between two distinct modes of TGF-?1 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-?1 in fibrotic diseases in vivo, as well as novel prognostic and therapeutic approaches for diseases with TGF-? dysregulation.

SUBMITTER: Venkatraman L

PROVIDER: S-EPMC3433618 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.

Venkatraman Lakshmi L Chia Ser-Mien SM Narmada Balakrishnan Chakrapani BC White Jacob K JK Bhowmick Sourav S SS Forbes Dewey C C So Peter T PT Tucker-Kellogg Lisa L Yu Hanry H

Biophysical journal 20120901 5

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 individu ...[more]

PMID: 23009856

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Project description:Castration experiments in rodents show that the stromal vasculature is critical to the androgen-mediated prostate growth regulation. However, the role of angiogenesis inhibitors, such as thrombospondin-1 (TSP-1), in this process is unclear. TSP-1 is a multifunctional glycoprotein that can function as a potent angiogenesis inhibitor and an in vivo activator of latent transforming growth factor-beta (TGF-beta) in some tissues. On the basis of these observations, we hypothesized that TSP-1 regulated androgen withdrawal-induced prostate regression and that this process was mediated not only through antiangiogenic activity but also through TGF-beta activation. To test this, we evaluated angiogenic activity in human prostate epithelial and stromal cells treated with androgens and hypoxia in vitro. TSP-1 knockout mice were characterized to investigate the in vivo functions of TSP-1. In vitro, we found that androgens and hypoxia differentially regulated TSP-1 and angiogenic activity. Androgens stimulated normal epithelial cell, but inhibited normal stromal cell, angiogenic activity. Conversely, hypoxia stimulated stromal while inhibiting epithelial activity. Thus, in vivo, net angiogenic activity must reflect cellular interactions. And, we found that media conditioned by epithelial cells grown under normoxic conditions stimulated stromal cell angiogenic activity, and if epithelial cells were grown under hypoxic conditions, stromal activity was further increased. TSP-1 levels, however, were unchanged. In vivo, TSP-1 loss in a mouse model led to prostate epithelial hyperplasia by 3 months of age with only a modest stromal effect. Androgens suppressed TSP-1 as expression increased after castration both in normal mouse prostate and in human prostate cancer tissues. In addition, TSP-1 expression corresponded to increased TGF-beta activation in mouse tissues, specifically in the stromal compartment. These data show a critical role for TSP-1 in prostate epithelial and stromal growth regulation through angiogenic inhibition and activation of latent TGF-beta. Therefore, loss of TSP-1 during tumorigenesis would eliminate two barriers to cancer progression.

Dataset Information

Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-?1.

Publications

Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.

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