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The role of specific Smad linker region phosphorylation in TGF-beta mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle
Muhamad A. Rostam1,2; Danielle Kamato1; Terence J. Piva3; Wenhua Zheng5,6; Peter J. Little1,7; Narin Osman1,4
2016-08
Source PublicationCELLULAR SIGNALLING
ISSN0898-6568
Volume28Issue:8Pages:956-966
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-beta (TGF-beta) 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-beta 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-beta. In addition ERK, p38, PI3K and CDK were found to differentially regulate mRNA expression of each enzyme. Four individual residues in the TGF-beta 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.

KeywordTransforming Growth Factor-beta Glycosaminoglycan Atherosclerosis Vascular Smooth Muscle Signalling Smad
DOI10.1016/j.cellsig.2016.05.002
Indexed BySCIE
WOS Research AreaCell Biology
WOS SubjectCell Biology
WOS IDWOS:000378670900018
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Cited Times [WOS]:19   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Diabetes Complications Group, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia
2.International Islamic University Malaysia, Kuala Lumpur 53100, Malaysia
3.Discipline of Cell Biology, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia
4.Department of Medicine and Immunology, Central and Eastern Clinical School, Monash University, Melbourne, Victoria 3800, Australia
5.State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Guangzhou, China
6.Faculty of Health Sciences, University of Macau, Taipa, Macau, China
7.School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland 4102, Australia
Recommended Citation
GB/T 7714
Muhamad A. Rostam,Danielle Kamato,Terence J. Piva,et al. The role of specific Smad linker region phosphorylation in TGF-beta mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle[J]. CELLULAR SIGNALLING,2016,28(8):956-966.
APA Muhamad A. Rostam,Danielle Kamato,Terence J. Piva,Wenhua Zheng,Peter J. Little,&Narin Osman.(2016).The role of specific Smad linker region phosphorylation in TGF-beta mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle.CELLULAR SIGNALLING,28(8),956-966.
MLA Muhamad A. Rostam,et al."The role of specific Smad linker region phosphorylation in TGF-beta mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle".CELLULAR SIGNALLING 28.8(2016):956-966.
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