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Autocrine Transforming Growth Factor β Signaling Regulates Extracellular Signal-regulated Kinase 1/2 Phosphorylation via Modulation of Protein Phosphatase 2A Expression in Scleroderma Fibroblasts

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dc.contributor.author Samuel, Glady H en_US
dc.contributor.author Bujor, Andreea M en_US
dc.contributor.author Nakerakanti, Sashidhar S en_US
dc.contributor.author Hant, Faye N en_US
dc.contributor.author Trojanowska, Maria en_US
dc.date.accessioned 2012-01-09T14:21:32Z
dc.date.available 2012-01-09T14:21:32Z
dc.date.copyright 2010 en_US
dc.date.issued 2010-12-06 en_US
dc.identifier.citation Samuel, Glady H, Andreea M Bujor, Sashidhar S Nakerakanti, Faye N Hant, Maria Trojanowska. "Autocrine Transforming Growth Factor β Signaling Regulates Extracellular Signal-regulated Kinase 1/2 Phosphorylation via Modulation of Protein Phosphatase 2A Expression in Scleroderma Fibroblasts" Fibrogenesis & Tissue Repair 3:25. (2010) en_US
dc.identifier.issn 1755-1536 en_US
dc.identifier.uri http://hdl.handle.net/2144/2758
dc.description.abstract BACKGROUND. During 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. RESULTS. We 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. CONCLUSIONS. Taken 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. en_US
dc.description.sponsorship National Institutes of Health (AR-44883) en_US
dc.language.iso en en_US
dc.publisher BioMed Central en_US
dc.rights Copyright 2010 Samuel et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. en_US
dc.title Autocrine Transforming Growth Factor β Signaling Regulates Extracellular Signal-regulated Kinase 1/2 Phosphorylation via Modulation of Protein Phosphatase 2A Expression in Scleroderma Fibroblasts en_US
dc.type article en_US
dc.identifier.doi 10.1186/1755-1536-3-25 en_US
dc.identifier.pubmedid 21134273 en_US
dc.identifier.pmcid 3008687 en_US


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