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

Lakshmi Venkatraman¹, Ser-Mien Chia, Balakrishnan Chakrapani Narmada

¹Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore.

Biophysical Journal

|September 27, 2012

Summary

This summary is machine-generated.

Transforming growth factor-β1 (TGF-β1) activation exhibits bistable switch-like behavior. Increasing plasmin (PLS) unexpectedly decreases TGF-β1 activation by disrupting thrombospondin-1 (TSP1) pathways, impacting fibrotic diseases.

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Area of Science:

Biochemistry
Cell Biology
Systems Biology

Background:

Transforming growth factor-β1 (TGF-β1) regulates key cellular processes and is implicated in fibrosis and cancer.
Extracellular activation of latent TGF-β1 offers spatiotemporal control, but activator crosstalk is poorly understood.
Plasmin (PLS) and thrombospondin-1 (TSP1) are known TGF-β1 activators, but their interplay is not fully elucidated.

Purpose of the Study:

To investigate the interplay between plasmin (PLS) and thrombospondin-1 (TSP1) in TGF-β1 activation using a systems-level approach.
To model and experimentally validate the proposed mechanisms of TGF-β1 activation influenced by PLS and TSP1.
To elucidate the switch-like behavior in TGF-β1 activation and its implications for fibrotic diseases.

Main Methods:

Mathematical modeling and simulations to predict the dynamics of TGF-β1 activation.
In vitro experiments using rat hepatocytes and hepatic stellate cells.
Analysis of proteolytic cleavage, dose-response, and hysteresis to validate model predictions.

Main Results:

Model simulations predicted a switch-like bistable transition in TGF-β1 activation, inversely correlated with PLS and TSP1 levels.
Increasing PLS was predicted to decrease TGF-β1 activation by breaking a TSP1-mediated positive feedback loop.
In vitro experiments confirmed that PLS treatment cleaves TSP1 and reduces TGF-β1 activation, demonstrating bistability and hysteresis.

Conclusions:

TGF-β1 activation exhibits switch-like behavior driven by competition between TSP1-mediated high activation and PLS-mediated low activation modes.
This bistability provides an explanation for observed effects of the plasminogen activation system on TGF-β1 in fibrotic diseases.
The findings suggest novel prognostic and therapeutic strategies for diseases involving TGF-β1 dysregulation.