Fibrillin-1 regulates the bioavailability of TGFβ1

We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta 1, a powerful cytokine that modulates cell survival and phenotype. Altered TGF beta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGF beta 1, thereby stimulating TGF beta receptor-mediated Smad2 signaling. This altered TGF beta 1 bioavailability does not require intact cells, proteolysis, or the altered expression of TGF beta 1 or its receptors. Mass spectrometry revealed that a fibrillin-1 fragment containing the TGF beta 1-releasing sequence specifically associates with full-length fibrillin-1 in cell layers. Solid-phase and BIAcore binding studies showed that this fragment interacts strongly and specifically with N-terminal fibrillin-1, thereby inhibiting the association of C-terminal latent TGF beta-binding protein 1 ( a component of the large latent complex [LLC]) with N-terminal fibrillin-1. By releasing LLC from micro. brils, the fibrillin-1 sequence encoded by exons 44-49 can contribute to MFS and related diseases.