Autocrine transforming growth factor β signaling regulates extracellular signal-regulated kinase 1/2 phosphorylation via modulation of protein phosphatase 2A expression in scleroderma fibroblasts.
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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DOI：
10.1186/1755-1536-3-25
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发表时间：
2010-12-06
期刊：
影响因子：
--
通讯作者：
Trojanowska M
中科院分区：
文献类型：
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作者：
Samuel GH;Bujor AM;Nakerakanti SS;Hant FN;Trojanowska M
在硬皮病（SSc）发病过程中，成纤维细胞获得活化表型，其特征在于细胞外基质（ECM）的产生增加和包括细胞外信号相关激酶（ERK 1/2）在内的几种主要信号通路的组成性活化。一些研究已经阐明了ERK 1/2在SSc纤维化中的作用，然而其在SSc成纤维细胞中的长期活化的机制仍然未知。蛋白磷酸酶2A（PP 2A）是一种关键的丝氨酸苏氨酸磷酸酶，负责多种信号分子的去磷酸化。最近发表的微阵列数据从培养的SSc成纤维细胞表明，PP 2A的催化亚基（C-亚基）在SSc下调。在这项研究中，我们研究了PP 2A在SSc成纤维细胞中ERK 1/2磷酸化和基质产生的作用和调节。我们首次发现PP 2A mRNA和蛋白表达在SSc成纤维细胞中显著降低，并与ERK 1/2磷酸化和胶原蛋白表达的增加相关。此外，转化生长因子β（TGFβ），一种与SSc纤维化有关的主要促纤维化细胞因子，下调健康成纤维细胞中的PP 2A表达。利用PP 2A特异性小干扰RNA（siRNA）来证实PP 2A在真皮成纤维细胞中ERK 1/2去磷酸化中的作用。因此，使用可溶性重组TGFβ受体II（SRII）阻断SSc成纤维细胞中的自分泌TGFβ信号传导恢复了PP 2A水平，并降低了ERK 1/2磷酸化和胶原蛋白表达。此外，我们观察到在SSc成纤维细胞中抑制ERK 1/2增加PP 2A表达，表明ERK 1/2磷酸化也有助于维持低水平的PP 2A，导致ERK 1/2磷酸化的进一步扩增。总之，这些研究表明，SSc中PP 2A水平降低是组成性激活自分泌TGFβ信号传导的结果，并可能有助于增强SSc成纤维细胞中ERK 1/2的磷酸化和基质产生。
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. 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. 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.