| Abstract | We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta 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 TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling. This altered TGFbeta1 bioavailability does not require intact cells, proteolysis, or the altered expression of TGFbeta1 or its receptors. Mass spectrometry revealed that a fibrillin-1 fragment containing the TGFbeta1-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 TGFbeta-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. |
| Authors | Shazia S Chaudhry, Stuart A Cain, Amanda Morgan, Sarah L Dallas, C Adrian Shuttleworth, Cay M Kielty
(Affiliation: Wellcome Trust Centre for Cell-Matrix Research, UK Centre for Tissue Engineering, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK.)
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| Journal | The Journal of cell biology
(J Cell Biol)
Vol. 176
Issue 3
Pg. 355-67
(Jan 29 2007)
ISSN: 0021-9525 United States |
| PMID | 17242066
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Microfilament Proteins
- Peptide Fragments
- Receptors, Transforming Growth Factor beta
- Recombinant Proteins
- SMAD2 protein, human
- Smad2 Protein
- Transforming Growth Factor beta1
- fibrillin
- TGF-beta type I receptor
- Activin Receptors, Type I
- Protein-Serine-Threonine Kinases
- transforming growth factor-beta type II receptor
|
| Topics |
- Activin Receptors, Type I
(metabolism)
- Cell Line
- Gene Expression
(physiology)
- Humans
- Marfan Syndrome
(metabolism)
- Mass Spectrometry
- Microfibrils
(metabolism)
- Microfilament Proteins
(chemistry, genetics, metabolism)
- Peptide Fragments
(metabolism)
- Protein Binding
- Protein Structure, Tertiary
- Protein-Serine-Threonine Kinases
- Receptors, Transforming Growth Factor beta
(metabolism)
- Recombinant Proteins
(chemistry, genetics, metabolism)
- Signal Transduction
(physiology)
- Smad2 Protein
(metabolism)
- Transforming Growth Factor beta1
(metabolism)
|
