Flavopiridol Inhibits TGF-<i>β</i>-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Rostam, Muhamad Ashraf; Shajimoon, Aravindra; Kamato, Danielle; Mitra, Partha; Piva, Terrence J.; Getachew, Robel; Cao, Yanshuo; Zheng, Wenhua; Osman, Narin; Little, Peter J.

doi:10.1124/jpet.117.244483

Cited by 30 publications

(33 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 52%

“…Former studies using activin A and a human neuroblastoma cell line demonstrated that the expression of some TGFβ superfamily target genes induced by ALK4-activin A did not require promoter bindings of SMAD2/3 [10]. By taking into consideration that of the XYLT1 promoter does not provide the according Smad binding site [29], but Smad2 linker phosphorylation was shown to enhance the nuclear localisation of Smad2 proteins [55], we presume that a potential activin A-ALK4 signalling pathway in NHDF is transduced by the MAPK JNK, p38 and ERK pathways and potential phosphorylation of the Smad2 linker region, promoting the nuclear entrance and favoured binding of Smad2 to the former identified transcription factors AP1 and SP1/3, known to increase XYLT1 expression [28,29,[58][59][60][61].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Plümers

Fischer

et al. 2020

Biomolecules

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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

Plümers

Fischer

et al. 2020

Biomolecules

View full text Add to dashboard Cite

show abstract

“…Thrombin signalling pathways leads to proteoglycan synthesis, GAG elongation [10] and an increase in the mRNA expression of GAG synthesizing genes [11]. TGF-β mediated proteoglycan synthesis [20,32] and GAG gene expression [19,21] are regulated by the phosphorylation of transcription factor Smad2 in the linker region. Multiple signalling pathways are involved in Smad2 linker region phosphorylation [3,8].…”

Section: Discussionmentioning

confidence: 99%

“…in an in vitro model of atherosclerosis we showed that linker region phosphorylation drives the expression of genes for the enzymes and transferases responsible for the synthesis of the biglycan [19][20][21].…”

Section: Introductionmentioning

confidence: 94%

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

Kamato

Burch

Zhou

et al. 2019

Cellular Signalling

Self Cite

View full text Add to dashboard Cite

show abstract

“…TGF-β family ligands exert their signal transduction by binding to cell-surface receptors, with predominantly intrinsic serine/threonine kinase activity. TGF-β via its cognate receptor transduces signals via Smad-dependent and Smad-independent pathways (96,97,98,99). Here we discuss how ROS interferes with Smad-dependent and -independent signalling pathways to regulate downstream gene expression.…”

Section: The Role Of Nox/ros In Gpcr Transactivation Of Tgfbr1mentioning

confidence: 99%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Cited by 30 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

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

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

Contact Info

Product

Resources

About