Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 37, Issue 4, Pages 485-493Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2006-0439OC
Keywords
focal adhesion complex; hydrogen peroxide-inducible clone 5; nuclear translocation; paxillin; vinculin
Funding
- NHLBI NIH HHS [R01 HL073929-03, R01 HL079320-02, R01 HL079320-04, R01 HL073929, R01 HL79320, R01 HL079320-03, R01 HL079320, R01 HL073929-04] Funding Source: Medline
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Transforming growth factor (TGF)-beta 1 activity has been shown to increase vascular endothelial barrier permeability, which is believed to precede several pathologic conditions, including pulmonary edema and vessel inflammation. In endothelial monolayers, TGF-beta 1 increases permeability, and a number of studies have demonstrated the alteration of cell-cell contacts by TGF-beta 1. We hypothesized that focal adhesion complexes also likely contribute to alterations in endothelial permeability. We examined early signal transduction events associated with rapid changes in monolayer permeability and the focal adhesion complex of bovine pulmonary artery endothelial cells. Western blotting revealed rapid tyrosine phosphorylation of focal adhesion kinase (FAK) and Src kinase in response to TGF-beta 1; inhibition of both of these kinases using pp2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), ameliorates TGF-beta 1-induced monolayer permeability. Activation of FAK/Src requires activation of the epidermal growth factor receptor downstream of the TGF-beta receptors, and is blocked by the epidermal growth factor receptor inhibitor AG1478. Immunohistochemistry showed that actin and the focal adhesion proteins paxillin, vinculin, and hydrogen peroxide-inducible clone-5 (Hic-S) are rearranged in response to TGF-beta 1; these proteins are released from focal adhesion complexes. Rearrangement of paxillin and vinculin by TGF-beta 1 is not blocked by the FAK/Src inhibitor, pp2, or by SB431542 inhibition of the TGF-beta type I receptor, anaplastic lymphoma kinase 5; however, pp1 (4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d] pyrimidine), which inhibits both type I and type II TGF-beta receptors, does block paxillin and vinculin rearrangement. Hic-5 protein rearrangement requires FAK/Src activity. Together, these results suggest that TGF-beta 1-induced monolayer permeability involves focal adhesion and cytoskeletal rearrangement through both FAK/Src-dependent and -independent pathways.
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