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Published online
doi:10.1083/jcb.200608167
The Journal of Cell Biology, Vol. 176, No. 3, 355-367
The Rockefeller University Press, 0021-9525 $30.00
© Chaudhry et al.
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Article

Fibrillin-1 regulates the bioavailability of TGFß1



Shazia S. Chaudhry1,2, Stuart A. Cain1, Amanda Morgan1, Sarah L. Dallas3, C. Adrian Shuttleworth1, and Cay M. Kielty1,2

1 Wellcome Trust Centre for Cell-Matrix Research and 2 UK Centre for Tissue Engineering, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK
3 Department of Oral Biology, School of Dentistry, University of Missouri, Kansas City, MO 64108

Correspondence to Cay M. Kielty: cay.kielty{at}manchester.ac.uk

We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) ß1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFß 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 TGFß1, thereby stimulating TGFß receptor–mediated Smad2 signaling. This altered TGFß1 bioavailability does not require intact cells, proteolysis, or the altered expression of TGFß1 or its receptors. Mass spectrometry revealed that a fibrillin-1 fragment containing the TGFß1-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 TGFß-binding protein 1 (a component of the large latent complex [LLC]) with N-terminal fibrillin-1. By releasing LLC from microfibrils, the fibrillin-1 sequence encoded by exons 44–49 can contribute to MFS and related diseases.

Abbreviations used in this paper: ANOVA, analysis of variance; cbEGF, calcium-binding EGF; HDF, human dermal fibroblast; LAP, latency-associated propeptide; LLC, large latent complex; LTBP, latent TGFß-binding protein; MFS, Marfan syndrome; SLC, small latent complex; TGFßR, TGFß receptor; TSP-1, thrombospondin-1.


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