Novartis Institutes of Biomedical Research, Respiratory Disease Area, Horsham, RH12 5AB, United Kingdom.
J Biol Chem. 2011 Apr 15;286(15):12912-23. doi: 10.1074/jbc.M110.143693. Epub 2011 Feb 18.
Discoidin domain receptors (DDRs) DDR1 and DDR2 are receptor tyrosine kinases with the unique ability among receptor tyrosine kinases to respond to collagen. Several signaling molecules have been implicated in DDR signaling, including Shp-2, Src, and MAPK pathways, but a detailed understanding of these pathways and their transcriptional targets is still lacking. Similarly, the regulation of the expression of DDRs is poorly characterized with only a few inflammatory mediators, such as lipopolysaccharide and interleukin-1β identified as playing a role in DDR1 expression. DDRs have been reported to induce the expression of various genes including matrix metalloproteinases and bone morphogenetic proteins, but the regulatory mechanisms underlying DDR-induced gene expression remain to be determined. The aim of the present work was to elucidate the molecular mechanisms implicated in the expression of DDRs and to identify DDR-induced signaling pathways and target genes. Our data show that collagen I induces the expression of DDR1 in a dose- and time-dependent manner in primary human lung fibroblasts. Furthermore, activation of DDR2, JAK2, and ERK1/2 MAPK signaling pathways was essential for collagen I-induced DDR1 and matrix metalloproteinase 10 expression. Finally, inhibition of the ERK1/2 pathway abrogated DDR1 expression by blocking the recruitment of the transcription factor polyoma enhancer A-binding protein 3 to the DDR1 promoter. Our data provide new insights into the molecular mechanisms of collagen I-induced DDR1 expression and demonstrate an important role for ERK1/2 activation and the recruitment of polyoma enhancer-A binding protein 3 to the DDR1 promoter.
Discoidin domain receptors (DDRs) DDR1 and DDR2 are receptor tyrosine kinases with the unique ability among receptor tyrosine kinases to respond to collagen. Several signaling molecules have been implicated in DDR signaling, including Shp-2, Src, and MAPK pathways, but a detailed understanding of these pathways and their transcriptional targets is still lacking. Similarly, the regulation of the expression of DDRs is poorly characterized with only a few inflammatory mediators, such as lipopolysaccharide and interleukin-1β identified as playing a role in DDR1 expression. DDRs have been reported to induce the expression of various genes including matrix metalloproteinases and bone morphogenetic proteins, but the regulatory mechanisms underlying DDR-induced gene expression remain to be determined. The aim of the present work was to elucidate the molecular mechanisms implicated in the expression of DDRs and to identify DDR-induced signaling pathways and target genes. Our data show that collagen I induces the expression of DDR1 in a dose- and time-dependent manner in primary human lung fibroblasts. Furthermore, activation of DDR2, JAK2, and ERK1/2 MAPK signaling pathways was essential for collagen I-induced DDR1 and matrix metalloproteinase 10 expression. Finally, inhibition of the ERK1/2 pathway abrogated DDR1 expression by blocking the recruitment of the transcription factor polyoma enhancer A-binding protein 3 to the DDR1 promoter. Our data provide new insights into the molecular mechanisms of collagen I-induced DDR1 expression and demonstrate an important role for ERK1/2 activation and the recruitment of polyoma enhancer-A binding protein 3 to the DDR1 promoter.
盘状结构域受体 (DDRs) DDR1 和 DDR2 是受体酪氨酸激酶，具有受体酪氨酸激酶中独特的胶原反应能力。几种信号分子已被牵连到 DDR 信号中，包括 Shp-2、Src 和 MAPK 途径，但对这些途径及其转录靶点的详细了解仍很缺乏。同样，DDR 表达的调控特征很差，只有少数炎症介质，如脂多糖和白细胞介素-1β被确定为 DDR1 表达的作用物。DDRs 已被报道诱导多种基因的表达，包括基质金属蛋白酶和骨形态发生蛋白，但 DDR 诱导基因表达的调控机制仍有待确定。本工作的目的是阐明 DDR 表达中涉及的分子机制，并鉴定 DDR 诱导的信号通路和靶基因。我们的数据表明，胶原 I 以剂量和时间依赖的方式诱导原代人肺成纤维细胞中 DDR1 的表达。此外，DDR2、JAK2 和 ERK1/2 MAPK 信号通路的激活对于胶原 I 诱导的 DDR1 和基质金属蛋白酶 10 的表达是必需的。最后，ERK1/2 通路的抑制通过阻断转录因子多瘤增强子 A 结合蛋白 3 向 DDR1 启动子的募集，阻断 DDR1 表达。我们的数据提供了胶原 I 诱导 DDR1 表达的分子机制的新见解，并证明了 ERK1/2 激活和多瘤增强子-A 结合蛋白 3 向 DDR1 启动子募集的重要作用。
