Fibrillin-1 regulates the bioavailability of TGFβ1

Autor: Sarah L. Dallas, C. Adrian Shuttleworth, Stuart A. Cain, Amanda Morgan, Shazia S. Chaudhry, Cay M. Kielty
Rok vydání: 2007
Předmět:
musculoskeletal diseases
congenital
hereditary
and neonatal diseases and abnormalities
Fibrillin-1
medicine.medical_treatment
Proteolysis
Receptor
Transforming Growth Factor-beta Type I
Gene Expression
Smad2 Protein
macromolecular substances
Protein Serine-Threonine Kinases
030204 cardiovascular system & hematology
Biology
Fibrillins
Mass Spectrometry
Article
Cell Line
Marfan Syndrome
Transforming Growth Factor beta1
Extracellular matrix
03 medical and health sciences
0302 clinical medicine
medicine
Extracellular
Humans
cardiovascular diseases
skin and connective tissue diseases
Receptor
Research Articles
030304 developmental biology
0303 health sciences
medicine.diagnostic_test
Microfilament Proteins
Receptor
Transforming Growth Factor-beta Type II
Cell Biology
Molecular biology
Phenotype
Peptide Fragments
Recombinant Proteins
Protein Structure
Tertiary
3. Good health
Cytokine
Microfibrils
Activin Receptors
Type I
Receptors
Transforming Growth Factor beta
Fibrillin
Protein Binding
Signal Transduction
Transforming growth factor
Zdroj: The Journal of Cell Biology
ISSN: 1540-8140
0021-9525
DOI: 10.1083/jcb.200608167
Popis: 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.
Databáze: OpenAIRE
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