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The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle

Hyperelongation of glycosaminoglycan chains on proteoglycans facilitates increased lipoprotein binding in the blood vessel wall and the development of atherosclerosis. Increased mRNA expression of glycosaminoglycan chain synthesizing enzymes in vivo is associated with the development of atheroscle...

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Main Authors: Rostam, Muhamad Ashraf, Kamato, Danielle, Piva, Terence J., Zheng, Wenhua, Little, Peter J., Osman, Narin
Format: Article
Language:English
English
English
Published: Elsevier Inc. 2016
Subjects:
RM Therapeutics. Pharmacology
Online Access:http://irep.iium.edu.my/54563/7/8.%20Rostam%20et%20al%202016.pdf
http://irep.iium.edu.my/54563/8/54563-The%20role%20of%20specific%20Smad%20linker%20region%20phosphorylation_SCOPUS.pdf
http://irep.iium.edu.my/54563/9/54563-The%20role%20of%20specific%20Smad%20linker%20region%20phosphorylation_WOS.pdf
http://irep.iium.edu.my/54563/
http://www.sciencedirect.com/science/article/pii/S0898656816300997
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spelling my.iium.irep.545632017-02-01T08:21:32Z http://irep.iium.edu.my/54563/ The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle Rostam, Muhamad Ashraf Kamato, Danielle Piva, Terence J. Zheng, Wenhua Little, Peter J. Osman, Narin RM Therapeutics. Pharmacology Hyperelongation of glycosaminoglycan chains on proteoglycans facilitates increased lipoprotein binding in the blood vessel wall and the development of atherosclerosis. Increased mRNA expression of glycosaminoglycan chain synthesizing enzymes in vivo is associated with the development of atherosclerosis. In human vascular smooth muscle, transforming growth factor-β (TGF-β) regulates glycosaminoglycan chain hyperelongation via ERK and p38 as well as Smad2 linker region (Smad2L) phosphorylation. In this study, we identified the involvement of TGF-β receptor, intracellular serine/threonine kinases and specific residues on transcription factor Smad2L that regulate glycosaminoglycan synthesizing enzymes. Of six glycosaminoglycan synthesizing enzymes, xylosyltransferase-1, chondroitin sulfate synthase-1, and chondroitin sulfotransferase-1 were regulated by TGF- β. In addition ERK, p38, PI3K and CDK were found to differentially regulate mRNA expression of each enzyme. Four individual residues in the TGF-β receptor mediator Smad2L can be phosphorylated by these kinases and in turn regulate the synthesis and activity of glycosaminoglycan synthesizing enzymes. Smad2L Thr220 was phosphorylated by CDKs and Smad2L Ser250 by ERK. p38 selectively signalled via Smad2L Ser245. Phosphorylation of Smad2L serine residues induced glycosaminoglycan synthesizing enzymes associated with glycosaminoglycan chain elongation. Phosphorylation of Smad2L Thr220 was associated with XT-1 enzyme regulation, a critical enzymein chain initiation. These findings provide a deeper understanding of the complex signalling pathways that contribute to glycosaminoglycan chain modification that could be targeted using pharmacological agents to inhibit the development of atherosclerosis. Elsevier Inc. 2016-08 Article REM application/pdf en http://irep.iium.edu.my/54563/7/8.%20Rostam%20et%20al%202016.pdf application/pdf en http://irep.iium.edu.my/54563/8/54563-The%20role%20of%20specific%20Smad%20linker%20region%20phosphorylation_SCOPUS.pdf application/pdf en http://irep.iium.edu.my/54563/9/54563-The%20role%20of%20specific%20Smad%20linker%20region%20phosphorylation_WOS.pdf Rostam, Muhamad Ashraf and Kamato, Danielle and Piva, Terence J. and Zheng, Wenhua and Little, Peter J. and Osman, Narin (2016) The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle. Cellular Signalling, 28 (8). pp. 956-966. ISSN 0898-6568 http://www.sciencedirect.com/science/article/pii/S0898656816300997 10.1016/j.cellsig.2016.05.002
institution Universiti Islam Antarabangsa Malaysia
building IIUM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider International Islamic University Malaysia
content_source IIUM Repository (IREP)
url_provider http://irep.iium.edu.my/
language English
English
English
topic RM Therapeutics. Pharmacology
spellingShingle RM Therapeutics. Pharmacology
Rostam, Muhamad Ashraf
Kamato, Danielle
Piva, Terence J.
Zheng, Wenhua
Little, Peter J.
Osman, Narin
The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle
description Hyperelongation of glycosaminoglycan chains on proteoglycans facilitates increased lipoprotein binding in the blood vessel wall and the development of atherosclerosis. Increased mRNA expression of glycosaminoglycan chain synthesizing enzymes in vivo is associated with the development of atherosclerosis. In human vascular smooth muscle, transforming growth factor-β (TGF-β) regulates glycosaminoglycan chain hyperelongation via ERK and p38 as well as Smad2 linker region (Smad2L) phosphorylation. In this study, we identified the involvement of TGF-β receptor, intracellular serine/threonine kinases and specific residues on transcription factor Smad2L that regulate glycosaminoglycan synthesizing enzymes. Of six glycosaminoglycan synthesizing enzymes, xylosyltransferase-1, chondroitin sulfate synthase-1, and chondroitin sulfotransferase-1 were regulated by TGF- β. In addition ERK, p38, PI3K and CDK were found to differentially regulate mRNA expression of each enzyme. Four individual residues in the TGF-β receptor mediator Smad2L can be phosphorylated by these kinases and in turn regulate the synthesis and activity of glycosaminoglycan synthesizing enzymes. Smad2L Thr220 was phosphorylated by CDKs and Smad2L Ser250 by ERK. p38 selectively signalled via Smad2L Ser245. Phosphorylation of Smad2L serine residues induced glycosaminoglycan synthesizing enzymes associated with glycosaminoglycan chain elongation. Phosphorylation of Smad2L Thr220 was associated with XT-1 enzyme regulation, a critical enzymein chain initiation. These findings provide a deeper understanding of the complex signalling pathways that contribute to glycosaminoglycan chain modification that could be targeted using pharmacological agents to inhibit the development of atherosclerosis.
format Article
author Rostam, Muhamad Ashraf
Kamato, Danielle
Piva, Terence J.
Zheng, Wenhua
Little, Peter J.
Osman, Narin
author_facet Rostam, Muhamad Ashraf
Kamato, Danielle
Piva, Terence J.
Zheng, Wenhua
Little, Peter J.
Osman, Narin
author_sort Rostam, Muhamad Ashraf
title The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle
title_short The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle
title_full The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle
title_fullStr The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle
title_full_unstemmed The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle
title_sort role of specific smad linker region phosphorylation in tgf-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle
publisher Elsevier Inc.
publishDate 2016
url http://irep.iium.edu.my/54563/7/8.%20Rostam%20et%20al%202016.pdf
http://irep.iium.edu.my/54563/8/54563-The%20role%20of%20specific%20Smad%20linker%20region%20phosphorylation_SCOPUS.pdf
http://irep.iium.edu.my/54563/9/54563-The%20role%20of%20specific%20Smad%20linker%20region%20phosphorylation_WOS.pdf
http://irep.iium.edu.my/54563/
http://www.sciencedirect.com/science/article/pii/S0898656816300997
_version_ 1643614577771937792
score 13.211869

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