title: Regulation of endothelial barrier function by TGF-β type I receptor ALK5: potential role of contractile mechanisms and heat shock protein 90.
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.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Antonov
authors.forename: Galina N
authors.initials: GN
authors.lastname: Antonova
authors.forename: Makiko
authors.initials: M
authors.lastname: Fujii
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
authors.forename: Vaishali
authors.initials: V
authors.lastname: Handa
authors.forename: John D
authors.initials: JD
authors.lastname: Catravas
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Verin
mesh_terms: D000256:Adenoviridae; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003487:Cyanoacrylates; D003599:Cytoskeleton; D003600:Cytosol; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D002148:Calmodulin-Binding Proteins; D003487:Cyanoacrylates; D055551:HSP27 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018994:Myosin Light Chains; D018125:Receptors, Transforming Growth Factor beta; C084545:Permabond 910; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse