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 D. Verin

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 2012

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Fingerprint

Dive into the research topics of 'Regulation of endothelial barrier function by TGF-β type I receptor ALK5: Potential role of contractile mechanisms and heat shock protein 90'. Together they form a unique fingerprint.

Cite this