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Research article

CCM2 and PAK4 act downstream of atrial natriuretic peptide signaling to promote cell spreading

Koichi Miura, Takashi Nojiri, Yoshiharu Akitake, Koji Ando, Shigetomo Fukuhara, Masahiro Zenitani, Toru Kimura, Jun Hino, Mikiya Miyazato, Hiroshi Hosoda, Kenji Kangawa
Biochemical Journal May 19, 2017, 474 (11) 1897-1918; DOI: 10.1042/BCJ20160841
Koichi Miura
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, JapanDepartment of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Takashi Nojiri
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Yoshiharu Akitake
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Koji Ando
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Shigetomo Fukuhara
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Masahiro Zenitani
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Toru Kimura
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Jun Hino
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Mikiya Miyazato
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Hiroshi Hosoda
Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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  • For correspondence: kangawa@ncvc.go.jphosoda.hiroshi.ri@ncvc.go.jp
Kenji Kangawa
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
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Abstract

Atrial natriuretic peptide (ANP) is a cardiac hormone released by the atrium in response to stretching forces. Via its receptor, guanylyl cyclase-A (GC-A), ANP maintains cardiovascular homeostasis by exerting diuretic, natriuretic, and hypotensive effects mediated, in part, by endothelial cells. Both in vivo and in vitro, ANP enhances endothelial barrier function by reducing RhoA activity and reorganizing the actin cytoskeleton. We established mouse endothelial cells that stably express GC-A and used them to analyze the molecular mechanisms responsible for actin reorganization. Stimulation by ANP resulted in phosphorylation of myosin light chain (MLC) and promotion of cell spreading. p21-activated kinase 4 (PAK4) and cerebral cavernous malformations 2 (CCM2), a scaffold protein involved in a cerebrovascular disease, were required for the phosphorylation of MLC and promotion of cell spreading by ANP. Finally, in addition to the GC domain, the kinase homology domain of GC-A was also required for ANP/GC-A signaling. Our results indicate that CCM2 and PAK4 are important downstream mediators of ANP/GC-A signaling involved in cell spreading, an important initial step in the enhancement of endothelial barrier function.

  • actin
  • endothelial cells
  • myosin
  • natriuretic peptide
  • RhoA
  • Abbreviations

    ANP,
    atrial natriuretic peptide;
    BPAEC,
    bovine pulmonary artery endothelial cell;
    CCMs,
    cerebral cavernous malformations;
    ECIS,
    electric cell-substrate impedance sensing;
    GC-A,
    guanylyl cyclase A;
    GCD,
    guanylyl cyclase domain;
    GEF,
    guanine nucleotide exchange factor;
    HPAEC,
    human pulmonary artery endothelial cell;
    KHD,
    kinase homology domain;
    LBD,
    ligand-binding domain;
    MLC,
    myosin light chain;
    MRCK,
    myotonic dystrophy kinase-related CDC42-binding kinase;
    NM-II,
    non-muscle myosin-II;
    PAK,
    p21 protein-activated kinase;
    PKGI,
    protein kinase G I;
    PM,
    plasma membrane;
    SVEC,
    SV40-transformed mouse endothelial cell;
    VASP,
    vasodilator-stimulated phosphoprotein
    • © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
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    June 2017

    Volume: 474 Issue: 11

    Biochemical Journal: 474 (11)
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    CCM2 and PAK4 act downstream of atrial natriuretic peptide signaling to promote cell spreading
    Koichi Miura, Takashi Nojiri, Yoshiharu Akitake, Koji Ando, Shigetomo Fukuhara, Masahiro Zenitani, Toru Kimura, Jun Hino, Mikiya Miyazato, Hiroshi Hosoda, Kenji Kangawa
    Biochemical Journal Jun 2017, 474 (11) 1897-1918; DOI: 10.1042/BCJ20160841
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    CCM2 and PAK4 act downstream of atrial natriuretic peptide signaling to promote cell spreading
    Koichi Miura, Takashi Nojiri, Yoshiharu Akitake, Koji Ando, Shigetomo Fukuhara, Masahiro Zenitani, Toru Kimura, Jun Hino, Mikiya Miyazato, Hiroshi Hosoda, Kenji Kangawa
    Biochemical Journal Jun 2017, 474 (11) 1897-1918; DOI: 10.1042/BCJ20160841

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    Keywords

    actin
    endothelial cells
    myosin
    natriuretic peptide
    RhoA

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