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/ http://irep.iium.edu.my/54563/ http://irep.iium.edu.my/54563/ 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

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spelling	iium-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 PeerReviewed 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
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
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/ http://irep.iium.edu.my/54563/ http://irep.iium.edu.my/54563/ 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
first_indexed	2023-09-18T21:17:12Z
last_indexed	2023-09-18T21:17:12Z
_version_	1777411641416089600

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

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