S100A4 and bone morphogenetic protein-2 codependently induce vascular smooth muscle cell migration via phospho-extracellular signal-regulated kinase and chloride intracellular channel 4.
S100A4 and bone morphogenetic protein-2 codependently induce vascular smooth muscle cell migration via phospho-extracellular signal-regulated kinase and chloride intracellular channel 4.
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DOI：
10.1161/circresaha.109.205120
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发表时间：
2009-09-25
影响因子：
20.1
通讯作者：
Rabinovitch M
中科院分区：
文献类型：
--
作者：
Spiekerkoetter E;Guignabert C;de Jesus Perez V;Alastalo TP;Powers JM;Wang L;Lawrie A;Ambartsumian N;Schmidt AM;Berryman M;Ashley RH;Rabinovitch M
S100A4/Mts1通过与晚期糖基化终末产物受体（RAGE）相互作用，参与人肺动脉平滑肌细胞（hPASMC）的运动。我们假设在肺动脉高压（PAH）中观察到的骨形态发生蛋白（BMP）受体II功能缺失可能会增强S100A4/Mts1介导的hPASMC运动。
S100A4/Mts1（500纳克/毫升）和BMP - 2（10纳克/毫升）都以一种新的共依赖方式诱导hPASMC迁移，即抗RAGE或BMPRII小干扰RNA（siRNA）会使对任一配体的反应丧失。两种配体均可诱导细胞外调节蛋白激酶（ERK）磷酸化，并且通过诱导基质金属蛋白酶2（MMP2）活性对运动是必需的，但磷酸化ERK1/2可被抗RAGE阻断，而不被BMPRII siRNA阻断。相反，BMPRII siRNA（而非抗RAGE）可降低细胞内氯离子通道4（CLIC4）的表达，CLIC4是对S100A4/Mts1或BMP - 2产生运动反应所必需的支架分子。CLIC4表达降低不会干扰S100A4/Mts1的内化或其与肌球蛋白重链IIA（MHCIIA）的相互作用，但会改变MHCIIA和肌动蛋白丝的排列，产生空泡样外观。这种异常与运动细胞中板状伪足收缩和伸展所需的小GTP酶RhoA和Rac1的外周分布减少和/或激活延迟有关。
我们的研究表明单一配体（BMP - 2或S100A4/Mts1）如何募集多个细胞表面受体来传递信号，协调最终产生功能性反应（即细胞运动）的事件。我们推测这种受到精细调控的过程限制了来自多个配体的信号，但在疾病中可能会被破坏。
S100A4/Mts1 is implicated in motility of human pulmonary artery smooth muscle cells (hPASMC), through an interaction with the receptor for advanced glycation end products (RAGE). We hypothesized that S100A4/Mts1-mediated hPASMC motility might be enhanced by loss of function of bone morphogenetic protein (BMP) receptor (R) II, observed in pulmonary arterial hypertension (PAH). Both S100A4/Mts1 (500ng/ml) and BMP-2 (10ng/ml) induce migration of hPASMCS in a novel co-dependent manner, in that the response to either ligand is lost with anti-RAGE or BMPRII siRNA. Phosphorylation of ERK is induced by both ligands and is required for motility by inducing MMP2 activity, but phosphoERK1/2 is blocked by anti-RAGE and not by BMPRII siRNA. In contrast, BMPRII siRNA, but not anti-RAGE, reduces expression of intracellular chloride channel 4 (CLIC4), a scaffolding molecule necessary for motility in response to S100A4/Mts1 or BMP-2. Reduced CLIC4 expression does not interfere with S100A4/Mts1 internalization or its interaction with myosin heavy chain IIA (MHCIIA), but does alter alignment of MHCIIA and actin filaments creating the appearance of vacuoles. This abnormality is associated with reduced peripheral distribution and/or delayed activation of RhoA and Rac1, small GTPases required for retraction and extension of lamellipodiae in motile cells. Our studies demonstrate how a single ligand (BMP-2 or S100A4/Mts1) can recruit multiple cell surface receptors to relay signals that coordinate events culminating in a functional response, i.e., cell motility. We speculate that this carefully controlled process limits signals from multiple ligands, but could be subverted in disease.