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Published on: October 27, 2020
Augmented binding and activation of latent transforming growth factor-beta by a tryptic fragment of latency
1Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.
Abstract:
Transforming growth factor-beta (TGF-beta) is secreted in a latent form; thus, activation is critical for the control of TGF-beta action. Latent TGF-beta exists in a complex in which mature TGF-beta is noncovalently linked to latency associated peptide (LAP) and latent TGF-beta binding protein (LTBP) complex. We have shown that latent TGF-beta is efficiently activated in heterotypic cultures of endothelial cells (ECs) and smooth muscle cells (SMCs). Under those conditions, LAP plays an important role in targeting latent TGF-beta to the surface of SMCs, and plasmin and calpain target it to the surface of ECs for activation. Here, we demonstrate in a homotypic culture system that fragments of LAP increase the binding of latent TGF-beta to ECs, resulting in its activation by cell-associated proteolysis. LAP fragments appear to bind to the cell surface and augment the binding of latent TGF-beta, independent of transglutaminase. These results suggest a unique mechanism for the activation of latent TGF-beta by proteolytic fragments of LAP. The mechanism may arise from degradation by elevated levels of proteases under certain conditions.
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