Bone Morphogenetic Protein 4 Promotes Vascular Smooth Muscle Contractility by Activating MicroRNA-21 (miR-21), which Down-regulates Expression of Family of Dedicator of Cytokinesis (DOCK) Proteins
Bone Morphogenetic Protein 4 Promotes Vascular Smooth Muscle Contractility by Activating MicroRNA-21 (miR-21), which Down-regulates Expression of Family of Dedicator of Cytokinesis (DOCK) Proteins
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DOI：
10.1074/jbc.m111.303156
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发表时间：
2012-02-03
影响因子：
4.8
通讯作者：
Hata, Akiko
中科院分区：
文献类型：
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作者：
Kang, Hara;Davis-Dusenbery, Brandi N.;Hata, Akiko
骨形态发生蛋白 4 (BMP4) 信号通路在血管平滑肌细胞 (vSMC) 收缩表型的促进和维持中发挥着关键作用。 BMP 受体基因的错误表达或失活突变可导致 vSMC 去分化，其特征是迁移和增殖增加，与血管增殖性疾病相关。之前我们证明，vSMCs 在 BMP4 处理后增加了 microRNA-21 (miR-21) 的生物合成，从而通过靶向程序性细胞死亡 4 (PDCD4) 诱导收缩基因表达。为了确定对 BMP4 诱导收缩表型至关重要的 miR-21 新靶点，在 vSMC 中表达生物素化的 miR-21，然后对与 miR-21 相关的 mRNA 进行亲和纯化。几乎所有胞质分裂贡献者 (DOCK) 180 相关蛋白超家族的成员都被确定为 miR-21 的靶标。 miR-21 下调 DOCK4、-5 和 -7 可抑制细胞迁移，并通过调节小 GTP 酶的活性促进细胞骨架组织。因此，本研究揭示了 BMP4-miR-21 轴通过 DOCK 家族蛋白对 vSMC 表型的调节机制。
The bone morphogenetic protein 4 (BMP4) signaling pathway plays a critical role in the promotion and maintenance of the contractile phenotype in vascular smooth muscle cell (vSMC). Misexpression or inactivating mutations of the BMP receptor gene can lead to dedifferentiation of vSMC characterized by increased migration and proliferation that is linked to vascular proliferative disorders. Previously we demonstrated that vSMCs increase microRNA-21 (miR-21) biogenesis upon BMP4 treatment, which induces contractile gene expression by targeting programmed cell death 4 (PDCD4). To identify novel targets of miR-21 that are critical for induction of the contractile phenotype by BMP4, biotinylated miR-21 was expressed in vSMCs followed by an affinity purification of mRNAs associated with miR-21. Nearly all members of the dedicator of cytokinesis (DOCK) 180-related protein superfamily were identified as targets of miR-21. Down-regulation of DOCK4, -5, and -7 by miR-21 inhibited cell migration and promoted cytoskeletal organization by modulating an activity of small GTPase. Thus, this study uncovers a regulatory mechanism of the vSMC phenotype by the BMP4-miR-21 axis through DOCK family proteins.