ArticleFibrogenesis & tissue repair2010
Autocrine transforming growth factor β signaling regulates extracellular signal-regulated kinase 1/2 phosphorylation via modulation of protein phosphatase 2A expression in scleroderma fibroblasts.
Article in Fibrogenesis & tissue repair, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.Rheumatology (Oxford, England) · 2024Trial
- The Role of Autophagy and Apoptosis in Affected Skin and Lungs in Patients with Systemic Sclerosis.International journal of molecular sciences · 2023Review
- Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis.Biomolecules · 2021Review
- Kelch-like protein 42 is a profibrotic ubiquitin E3 ligase involved in systemic sclerosis.The Journal of biological chemistry · 2020Article
- Microparticles in systemic sclerosis, targets or tools to control fibrosis: This is the question!Journal of scleroderma and related disorders · 2020Review
- Scar management in burn injuries using drug delivery and molecular signaling: Current treatments and future directions.Advanced drug delivery reviews · 2018Review
- Blocking protein phosphatase 2A signaling prevents endothelial-to-mesenchymal transition and renal fibrosis: a peptide-based drug therapy.Scientific reports · 2016Article
- Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac.Cell cycle (Georgetown, Tex.) · 2016Article
- Mysteries of TGF-β Paradox in Benign and Malignant Cells.Frontiers in oncology · 2014Review
- Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-β1 signaling.Journal of immunology (Baltimore, Md. : 1950) · 2012Article
- Acid sphingomyelinase deficiency contributes to resistance of scleroderma fibroblasts to Fas-mediated apoptosis.Journal of dermatological science · 2012Article
- Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts.Arthritis and rheumatism · 2012Article
- MEK/ERK inhibitors: proof-of-concept studies in lung fibrosis.Journal of cell communication and signaling · 2012Article
- The Role of TGF-β Receptors in Fibrosis.The open rheumatology journal · 2012Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundDuring scleroderma (SSc) pathogenesis, fibroblasts acquire an activated phenotype characterized by enhanced production of extracellular matrix (ECM) and constitutive activation of several major signaling pathways including extracellular signal-related kinase (ERK1/2). Several studies have addressed the role of ERK1/2 in SSc fibrosis however the mechanism of its prolonged activation in SSc fibroblasts is still unknown. Protein phosphatase 2A (PP2A) is a key serine threonine phosphatase responsible for dephosphorylation of a wide array of signaling molecules. Recently published microarray data from cultured SSc fibroblasts suggests that the catalytic subunit (C-subunit) of PP2A is downregulated in SSc. In this study we examined the role and regulation of PP2A in SSc fibroblasts in the context of ERK1/2 phosphorylation and matrix production.
resultsWe show for the first time that PP2A mRNA and protein expression are significantly reduced in SSc fibroblasts and correlate with an increase in ERK1/2 phosphorylation and collagen expression. Furthermore, transforming growth factor β (TGFβ), a major profibrotic cytokine implicated in SSc fibrosis, downregulates PP2A expression in healthy fibroblasts. PP2A-specific small interfering RNA (siRNA) was utilized to confirm the role of PP2A in ERK1/2 dephosphorylation in dermal fibroblasts. Accordingly, blockade of autocrine TGFβ signaling in SSc fibroblasts using soluble recombinant TGFβ receptor II (SRII) restored PP2A levels and decreased ERK1/2 phosphorylation and collagen expression. In addition, we observed that inhibition of ERK1/2 in SSc fibroblasts increased PP2A expression suggesting that ERK1/2 phosphorylation also contributes to maintaining low levels of PP2A, leading to an even further amplification of ERK1/2 phosphorylation.
conclusionsTaken together, these studies suggest that decreased PP2A levels in SSc is a result of constitutively activated autocrine TGFβ signaling and could contribute to enhanced phosphorylation of ERK1/2 and matrix production in SSc fibroblasts.
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Registered trials
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