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- Title
Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells.
- Authors
Kamato, Danielle; Rostam, Muhamad Ashraf; Piva, Terence J.; Babaahmadi Rezaei, Hossein; Getachew, Robel; Thach, Lyna; Bernard, Rebekah; Zheng, Wenhua; Little, Peter J.; Osman, Narin
- Abstract
Objectives Transforming growth factor ( TGF)-β regulates the function of vascular endothelial cells and may be involved in endothelial dysfunction. The canonical TGF-β pathway involves TGF-β receptor-mediated carboxy-terminal phosphorylation of Smad2; however, TGF-β signalling also activates numerous serine/threonine kinases that phosphorylate Smad2 in its linker region. The expression of phosphorylated Smad linker proteins were determined following TGF-β stimulation in the absence and presence of different serine/threonine kinase inhibitors in vascular endothelial cells. Methods Proteins were quantified by Western blotting using specific antibodies to individual phosphorylated Smad2 linker region residues. Key findings TGF-β mediated the phosphorylation of all four Smad2 linker region residues of interest. Erk and Jnk specifically phosphorylate Ser245 while all mitogen-activated protein kinases phosphorylate Ser250 and Ser255. Thr220 and Ser245 are phosphorylated by phosphoinositide 3 kinase ( PI3 K), while Ser255 was phosphorylated by the PI3 K/ Akt pathway. CDK and GSK-3 were shown to phosphorylate Thr220 and Ser245. TGF-β also mediated plasminogen activator inhibitor-1 gene expression that was attenuated by p38 and CDK inhibitors. Conclusions TGF-β-mediated phosphorylation of individual serine/threonine sites in the linker region of Smad2 occurs in a highly specific manner by kinases. These phosphorylations provide an opportunity to further understand a therapeutically targeted and very specific signalling pathway in vascular endothelial cells.
- Subjects
GROWTH factors; CYTOKINES; ENDOTHELIAL cells; DEPHOSPHORYLATION; PHOSPHORYLATION
- Publication
Journal of Pharmacy & Pharmacology, 2014, Vol 66, Issue 12, p1722
- ISSN
0022-3573
- Publication type
Article
- DOI
10.1111/jphp.12298