title: 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.
abstract: 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.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA.
authors.forename: Hara
authors.initials: H
authors.lastname: Kang
authors.forename: Brandi N
authors.initials: BN
authors.lastname: Davis-Dusenbery
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nguyen
authors.forename: Ashish
authors.initials: A
authors.lastname: Lal
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.forename: Linda
authors.initials: L
authors.lastname: Van Aelst
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lagna
authors.forename: Akiko
authors.initials: A
authors.lastname: Hata
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009119:Muscle Contraction / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D020690:GTPase-Activating Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009124:Muscle Proteins; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins