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

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1897-1918
Number of pages22
JournalBiochemical Journal
Issue number11
Publication statusPublished - Jun 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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