Decreased caveolin-1 levels contribute to fibrosis and deposition of extracellular IGFBP-5

Yukie Yamaguchi, Hidekata Yasuoka, Donna B. Stolz, Carol A. Feghali-Bostwick

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)957-969
Number of pages13
JournalJournal of Cellular and Molecular Medicine
Volume15
Issue number4
DOIs
Publication statusPublished - 2011 Apr
Externally publishedYes

Fingerprint

Insulin-Like Growth Factor Binding Protein 5
Caveolin 1
Fibrosis
Fibroblasts
Extracellular Matrix
Lipids

Keywords

  • Caveolin-1
  • Extracellular matrix
  • Fibrosis
  • Insulin-like growth factor binding protein-5

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

Cite this

Decreased caveolin-1 levels contribute to fibrosis and deposition of extracellular IGFBP-5. / Yamaguchi, Yukie; Yasuoka, Hidekata; Stolz, Donna B.; Feghali-Bostwick, Carol A.

In: Journal of Cellular and Molecular Medicine, Vol. 15, No. 4, 04.2011, p. 957-969.

Research output: Contribution to journalArticle

Yamaguchi, Yukie ; Yasuoka, Hidekata ; Stolz, Donna B. ; Feghali-Bostwick, Carol A. / Decreased caveolin-1 levels contribute to fibrosis and deposition of extracellular IGFBP-5. In: Journal of Cellular and Molecular Medicine. 2011 ; Vol. 15, No. 4. pp. 957-969.
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