Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells

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 numer...

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Main Authors:	Kamato, Danielle, Rostam, Muhamad Ashraf, Piva, Terence J., Rezaei, Hossein B., Getachew, Robel, Thach, Lyna, Bernard, Rebekah, Zheng, Wenhua, Little, Peter J., Osman, Narin
Format:	Article
Language:	English
Published:	Wiley 2014
Subjects:	QP Physiology RM Therapeutics. Pharmacology
Online Access:	http://irep.iium.edu.my/55283/ http://irep.iium.edu.my/55283/ http://irep.iium.edu.my/55283/ http://irep.iium.edu.my/55283/1/5.%20Kamato-2014-Transforming%20growth%20factor%20%CE%B2-media.pdf

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spelling	iium-552832017-03-23T03:36:24Z http://irep.iium.edu.my/55283/ Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells Kamato, Danielle Rostam, Muhamad Ashraf Piva, Terence J. Rezaei, Hossein B. Getachew, Robel Thach, Lyna Bernard, Rebekah Zheng, Wenhua Little, Peter J. Osman, Narin QP Physiology RM Therapeutics. Pharmacology 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 (PI3K), while Ser255 was phosphorylated by the PI3K/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. Wiley 2014-12 Article PeerReviewed application/pdf en http://irep.iium.edu.my/55283/1/5.%20Kamato-2014-Transforming%20growth%20factor%20%CE%B2-media.pdf Kamato, Danielle and Rostam, Muhamad Ashraf and Piva, Terence J. and Rezaei, Hossein B. and Getachew, Robel and Thach, Lyna and Bernard, Rebekah and Zheng, Wenhua and Little, Peter J. and Osman, Narin (2014) Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells. Journal of Pharmacy and Pharmacology, 66 (12). pp. 1722-1733. E-ISSN 2042-7158 http://onlinelibrary.wiley.com/doi/10.1111/jphp.12298/abstract 10.1111/jphp.12298
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English
topic	QP Physiology RM Therapeutics. Pharmacology
spellingShingle	QP Physiology RM Therapeutics. Pharmacology Kamato, Danielle Rostam, Muhamad Ashraf Piva, Terence J. Rezaei, Hossein B. Getachew, Robel Thach, Lyna Bernard, Rebekah Zheng, Wenhua Little, Peter J. Osman, Narin Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells
description	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 (PI3K), while Ser255 was phosphorylated by the PI3K/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.
format	Article
author	Kamato, Danielle Rostam, Muhamad Ashraf Piva, Terence J. Rezaei, Hossein B. Getachew, Robel Thach, Lyna Bernard, Rebekah Zheng, Wenhua Little, Peter J. Osman, Narin
author_facet	Kamato, Danielle Rostam, Muhamad Ashraf Piva, Terence J. Rezaei, Hossein B. Getachew, Robel Thach, Lyna Bernard, Rebekah Zheng, Wenhua Little, Peter J. Osman, Narin
author_sort	Kamato, Danielle
title	Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells
title_short	Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells
title_full	Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells
title_fullStr	Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells
title_full_unstemmed	Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells
title_sort	transforming growth factor β-mediated site-specific smad linker region phosphorylation in vascular endothelial cells
publisher	Wiley
publishDate	2014
url	http://irep.iium.edu.my/55283/ http://irep.iium.edu.my/55283/ http://irep.iium.edu.my/55283/ http://irep.iium.edu.my/55283/1/5.%20Kamato-2014-Transforming%20growth%20factor%20%CE%B2-media.pdf
first_indexed	2023-09-18T21:18:09Z
last_indexed	2023-09-18T21:18:09Z
_version_	1777411701425045504

Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells

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