Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes

Kamato, Danielle; Burch, Micah L; Zhou, Ying; Mohamed, Raafat; Stow, Jennifer L.; Osman, Narin; Zheng, Wenhua; Little, Peter J.

doi:10.1016/j.cellsig.2018.11.005

Cited by 24 publications

(31 citation statements)

References 49 publications

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“…Additionally, the cell-type specific activation of individual MAPK JNK, p38 and ERK has been demonstrated to phosphorylate the regulatory linker region of Smad2 protein [13,49]. As Smad signalling is critical to fibroblast activation and fibrosis induced by activin A [49,55], inhibition of Smad2 signalling by usage of MAPK inhibitors might have contributed to the suppressed XYLT1 expression increase in activin A-stimulated cells shown in this study. Several studies using human VSMC have demonstrated the dependency of PG synthesis on the phosphorylation of the Smad2 linker region.…”

Section: Discussionsupporting

confidence: 54%

“…The involvement of p38 MAPK in the TGFβ pathway promoted XT-I mRNA and the activity increase were observed in cultured human cardiac fibroblasts stimulated with TGFβ1 and corresponds with an elevated amount of digested GAG content in cardiac tissues from patients with myocardial fibrosis [27]. Additionally, in a recent study JNK and p38 were shown to be involved in growth factor thrombin or IL-1β-induced XYLT1 mRNA expression increase in vascular smooth-muscle cells or primary chondrocyte cells [43,49].…”

Section: Discussionmentioning

confidence: 92%

“…Several studies using human VSMC have demonstrated the dependency of PG synthesis on the phosphorylation of the Smad2 linker region. These studies especially highlighted Smad2 linker residue Thr220 regarding the transcriptional regulation of XT-I that can undergo phosphorylation by two of the three MAPKs p38, ERK and JNK after TGFβ or thrombin stimulation of VSMC [49,56]. As our results show that activin A-mediated XYLT1 expression increase is dependent on SMAD2 expression and involves the activity of MAPK JNK, p38 and ERK, and thus possibly JNK, p38 and ERK initiate non-canonical phosphorylation of the Smad2 linker region, which could have an inducible effect on XYLT1 mRNA expression in NHDF.…”

Section: Discussionmentioning

confidence: 99%

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Activin A-Mediated Regulation of XT-I in Human Skin Fibroblasts

Plümers

Fischer

et al. 2020

Biomolecules

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Fibrosis is a fundamental feature of systemic sclerosis (SSc) and is characterized by excessive accumulation of extracellular matrix components like proteoglycans (PG) or collagens in skin and internal organs. Serum analysis from SSc patients showed an increase in the enzyme activity of xylosyltransferase (XT), the initial enzyme in PG biosynthesis. There are two distinct XT isoforms—XT-I and XT-II—in humans, but until now only XT-I is associated with fibrotic remodelling for an unknown reason. The aim of this study was to identify new XT mediators and clarify the underlying mechanisms, in view of developing putative therapeutic anti-fibrotic interventions in the future. Therefore, we used different cytokines and growth factors, small molecule inhibitors as well as small interfering RNAs, and assessed the cellular XT activity and XYLT1 expression in primary human dermal fibroblasts by radiochemical activity assays and qRT-PCR. We identified a new function of activin A as a regulator of XYLT1 mRNA expression and XT activity. While the activin A-induced XT-I increase was found to be mediated by activin A receptor type 1B, MAPK and Smad pathways, the activin A treatment did not alter the XYLT2 expression. Furthermore, we observed a reciprocal regulation of XYLT1 and XYLT2 transcription after inhibition of the activin A pathway components. These results improve the understanding of the differential expression regulation of XYLT isoforms under pathological fibroproliferative conditions.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Activin A-Mediated Regulation of XT-I in Human Skin Fibroblasts

Plümers

Fischer

et al. 2020

Biomolecules

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“…While GPCR transactivation of EGFR requires MMP stimulation, the activation of TGFBR1 occurs through cytoskeletal rearrangement which activates ROCK signalling and cell-surface integrins ( 13 , 16 , 122 ). We previously found that the GPCR agonist thrombin transactivates the EGFR and TGFBR1 to stimulate the expression of enzymes involved in the hyperelongation of glycosaminoglycan chains on the proteoglycan, biglycan ( 123 , 124 ) which is associated with increased lipid retention in the vessel wall initiating atherosclerosis ( 125 , 126 ). We have described that GPCR transactivation of either receptor is occurring via completely different mechanisms and the identification of a common mechanism can attenuate all GPCR-mediated GAG chain elongation ( 127 , 128 ).…”

Section: Discussionmentioning

confidence: 99%

GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species

et al. 2019

Self Cite

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The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.

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“…According to the order of parameter and radiality from high to low as the standard, a total of 15 core proteins were screened, which includes the SMAD family variant 2 (SMAD2), CCAAT enhancer binding protein beta (CEBPB), conversion factor 1 (TGFB1), mitotic checkpoint serine/threonine protein kinase B (BUB1B), output 1 (XPO1), cell division cycle protein 27 (CDC27), early young granulocyte leukemia variant 1 (PML) transcription, protein phosphatase 2 support subunits X5 (PPP2R1B), cellar protein 1 (CAV1), autosomal histone lysine methylation transferase (EHMT2) 2, transforming growth factor beta receptor 1 (TGFbR1), histone (Hist1H2BM), retinol X receptor α (RXRA), adhesive protein complex (Rad21), and E3 ubiquitin protein ligase (Nedd4) (Figure 5). SMAD proteins encoded by their respective genes are signal transducers and transcriptional modulators that mediate multiple signaling pathways [17,18]. This protein mediates the signal of the transforming growth factor-(TGF-) beta, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation [19,20].…”

Section: Ppi Network Analysis and Core Disturbed Genementioning

confidence: 99%

Gene Expression Profiling and Biofunction Analysis of HepG2 Cells Targeted by Crocetin

Wen

Zhu

et al. 2021

Mediators of Inflammation

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Crocetin is a carotenoid extracted from Gardenia jasminoides, one of the most popular traditional Chinese medicines, which has been used in the prevention and treatment of various diseases. The present study is aimed at clarifying the effect of crocetin on gene expression profiling of HepG2 cells by RNA-sequence assay and further investigating the molecular mechanism underlying the multiple biofunctions of crocetin based on bioinformatics analysis and molecular evidence. Among a total 23K differential genes identified, crocetin treatment upregulated the signals of 491 genes (2.14% of total gene probes) and downregulated the signals of 283 genes (1.24% of total gene probes) by ≥2-fold. The Gene Ontology analysis enriched these genes mainly on cell proliferation and apoptosis (BRD4 and DAXX); lipid formation (EHMT2); cell response to growth factor stimulation (CYP24A1 and GCNT2); and growth factor binding (ABCB1 and ABCG1), metabolism, and signal transduction processes. The KEGG pathway analysis revealed that crocetin has the potential to regulate transcriptional misregulation, ABC transporters, bile secretion, alcoholism, systemic lupus erythematosus (SLE), and other pathways, of which SLE was the most significantly disturbed pathway. The PPI network was constructed by using the STRING online protein interaction database and Cytoscape software, and 21 core proteins were obtained. RT-qPCR datasets serve as the solid evidence that verified the accuracy of transcriptome sequencing results with the same change trend. This study provides first-hand data for comprehensively understanding crocetin targeting on hepatic metabolism and its multiple biofunctions.

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Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes

Abstract: Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes. Cls (2018),

Cited by 24 publications

References 49 publications

Activin A-Mediated Regulation of XT-I in Human Skin Fibroblasts

Activin A-Mediated Regulation of XT-I in Human Skin Fibroblasts

GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species

Gene Expression Profiling and Biofunction Analysis of HepG2 Cells Targeted by Crocetin

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