Document Detail


Decreased caveolin-1 levels contribute to fibrosis and deposition of extracellular IGFBP-5.
MedLine Citation:
PMID:  20345844     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Our previous studies have demonstrated increased expression of insulin-like growth factor binding protein-5 (IGFBP-5) in fibrotic tissues and IGFBP-5 induction of extracellular matrix (ECM) components. The mechanism resulting in increased IGFBP-5 in the extracellular milieu of fibrotic fibroblasts is unknown. Since Caveolin-1 (Cav-1) has been implicated to play a role in membrane trafficking and signal transduction in tissue fibrosis, we examined the effect of Cav-1 on IGFBP-5 internalization, trafficking and secretion. We demonstrated that IGFBP-5 localized to lipid rafts in human lung fibroblasts and bound Cav-1. Cav-1 was detected in the nucleus in IGFBP-5-expressing fibroblasts, within aggregates enriched with IGFBP-5, suggesting a coordinate trafficking of IGFBP-5 and Cav-1 from the plasma membrane to the nucleus. This trafficking was dependent on Cav-1 as fibroblasts from Cav-1 null mice had increased extracellular IGFBP-5, and as fibroblasts in which Cav-1 was silenced or lipid raft structure was disrupted through cholesterol depletion also had defective IGFBP-5 internalization. Restoration of Cav-1 function through administration of Cav-1 scaffolding peptide dramatically increased IGFBP-5 uptake. Finally, we demonstrated that IGFBP-5 in the ECM protects fibronectin from proteolytic degradation. Taken together, our findings identify a novel role for Cav-1 in the internalization and nuclear trafficking of IGFBP-5. Decreased Cav-1 expression in fibrotic diseases likely leads to increased deposition of IGFBP-5 in the ECM with subsequent reduction in ECM degradation, thus identifying a mechanism by which reduced Cav-1 and increased IGFBP-5 concomitantly contribute to the perpetuation of fibrosis.
Authors:
Yukie Yamaguchi; Hidekata Yasuoka; Donna B Stolz; Carol A Feghali-Bostwick
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of cellular and molecular medicine     Volume:  15     ISSN:  1582-4934     ISO Abbreviation:  J. Cell. Mol. Med.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-05-06     Completed Date:  2011-08-26     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  101083777     Medline TA:  J Cell Mol Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  957-69     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
Caveolin 1 / deficiency,  metabolism*
Cell Compartmentation
Cell Extracts
Cell Nucleus / metabolism,  ultrastructure
Cytoplasm / metabolism
Endocytosis
Extracellular Matrix / metabolism*
Extracellular Space / metabolism
Fibroblasts / metabolism,  pathology,  ultrastructure
Fibrosis
Humans
Insulin-Like Growth Factor Binding Protein 3 / metabolism
Insulin-Like Growth Factor Binding Protein 5 / metabolism*
Intracellular Space / metabolism
Mice
Mice, Inbred C57BL
Protein Binding
Protein Transport
Subcellular Fractions / metabolism
Grant Support
ID/Acronym/Agency:
AR050840/AR/NIAMS NIH HHS; R01 AR050840/AR/NIAMS NIH HHS; R01 AR050840-08/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Caveolin 1; 0/Cell Extracts; 0/Insulin-Like Growth Factor Binding Protein 3; 0/Insulin-Like Growth Factor Binding Protein 5
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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