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

Rostam, Muhamad A., Kamato, Danielle, Piva, Terence J., Zheng, Wenhua, 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: 956-966. doi:10.1016/j.cellsig.2016.05.002


Author Rostam, Muhamad A.
Kamato, Danielle
Piva, Terence J.
Zheng, Wenhua
Little, Peter J.
Osman, Narin
Title The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle
Journal name Cellular Signalling   Check publisher's open access policy
ISSN 1873-3913
0898-6568
Publication date 2016-08-01
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.cellsig.2016.05.002
Open Access Status Not Open Access
Volume 28
Issue 8
Start page 956
End page 966
Total pages 11
Place of publication Philadelphia, PA United States
Publisher Elsevier
Collection year 2017
Language eng
Abstract 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 enzyme in 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.
Keyword Transforming growth factor-β
Smad
Glycosaminoglycan
Atherosclerosis
Vascular smooth muscle
Signalling
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
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