Regulation of endothelial barrier function by TGF-β type I receptor ALK5: Potential role of contractile mechanisms and heat shock protein 90

Alexander S. Antonov, Galina N. Antonova, Makiko Fujii, Peter ten Dijke, Vaishali Handa, John D. Catravas, Alexander Dmitriyevich Verin

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Multifunctional cytokine transforming growth factor-beta (TGF-β1) plays a critical role in the pathogenesis of acute lung inflammation by controlling endothelial monolayer permeability. TGF-β1 regulates endothelial cell (EC) functions via two distinct receptors, activin receptor-like kinase 1 (ALK1) and activin receptor-like kinase 5 (ALK5). The precise roles of ALK1 and ALK5 in the regulation of TGF-β1-induced lung endothelium dysfunction remain mostly unknown. We now report that adenoviral infection with constitutively active ALK5 (caALK5), but not caALK1, induces EC retraction and that this receptor predominantly controls EC permeability. We demonstrate that ubiquitinated ALK5 and phosphorylated heat shock protein 27 (phospho-Hsp27) specifically accumulate in the cytoskeleton fraction, which parallels with microtubule collapse, cortical actin disassembly and increased EC permeability. We have found that ALK1 and ALK5 interact with heat shock protein 90 (Hsp90). Moreover, the Hsp90 inhibitor radicicol (RA) prevents accumulation of ubiquitinated caALK5 and phospho-Hsp27 in the cytoskeletal fraction and restore the decreased EC permeability induced by caALK5. We hypothesize that specific translocation of ubiquitinated ALK5 receptor into the cytoskeleton compartment due to its lack of degradation is the mechanism that causes the divergence of caALK1 and caALK5 signaling.

Original languageEnglish (US)
Pages (from-to)759-771
Number of pages13
JournalJournal of Cellular Physiology
Volume227
Issue number2
DOIs
StatePublished - Jan 1 2012

Fingerprint

HSP90 Heat-Shock Proteins
Endothelial cells
Activin Receptors
Endothelial Cells
Permeability
Cytoskeleton
HSP27 Heat-Shock Proteins
Microtubules
Transforming Growth Factor beta
Endothelium
TGF-beta type I receptor
Actins
Monolayers
Pneumonia
Cytokines
Degradation
Lung
Infection

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Regulation of endothelial barrier function by TGF-β type I receptor ALK5 : Potential role of contractile mechanisms and heat shock protein 90. / Antonov, Alexander S.; Antonova, Galina N.; Fujii, Makiko; ten Dijke, Peter; Handa, Vaishali; Catravas, John D.; Verin, Alexander Dmitriyevich.

In: Journal of Cellular Physiology, Vol. 227, No. 2, 01.01.2012, p. 759-771.

Research output: Contribution to journalArticle

Antonov, Alexander S. ; Antonova, Galina N. ; Fujii, Makiko ; ten Dijke, Peter ; Handa, Vaishali ; Catravas, John D. ; Verin, Alexander Dmitriyevich. / Regulation of endothelial barrier function by TGF-β type I receptor ALK5 : Potential role of contractile mechanisms and heat shock protein 90. In: Journal of Cellular Physiology. 2012 ; Vol. 227, No. 2. pp. 759-771.
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