Natriuretic peptide receptor-C releases and activates guanine nucleotide-exchange factor H1 in a ligand-dependent manner

• Published in: Biochemical and biophysical research communications Vol. 552; pp. 9 - 16
• Main Authors: Nishida, Mika, Miyamoto, Kenji, Abe, Shogo, Shimada, Maki, Shimizu, Yuki, Tsuji, Akihiko, Yuasa, Keizo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.05.2021
• Subjects: GEF-H1; NPR-C; Osteocrin; Protein-protein interaction; NPR; Osteocrin; NP; Protein-protein interaction; NPR-C; GST; GEF-H1; GC; NM
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.03.028

Although natriuretic peptide receptor-C (NPR-C) is involved in the clearance of natriuretic peptides from plasma, it also possesses other physiological functions, such as inhibition of adenylyl cyclase activity through Gαi. However, the physiological roles and intracellular signaling pathways of NPR-C have yet been not fully elucidated. In this study, we identified a RhoA-specific guanine nucleotide-exchange factor, GEF-H1, as a novel binding protein of NPR-C. We demonstrated that endogenous NPR-C interacted with GEF-H1 in HeLa cells, and that the interaction between NPR-C and GEF-H1 was dependent on a 37-amino acid cytoplasmic region of NPR-C. In contrast, another natriuretic peptide receptor, NPR-A, which includes the kinase homology and guanylyl cyclase domains in the intracellular region, did not interact with GEF-H1. We also revealed that the ligands of NPR-C (i.e., ANP, CNP, and osteocrin) caused dissociation of GEF-H1 from NPR-C. Furthermore, osteocrin treatment induced phosphorylation of GEF-H1 at Ser-886, enhanced the interaction of GEF-H1 with 14-3-3, and increased the amount of activated GEF-H1. These findings strongly supported that NPR-C may be involved in diverse physiological roles by regulating GEF-H1 signaling. •GEF-H1 was identified as a novel NPR-C-binding protein.•The ligands of NPR-C, CNP and osteocrin, caused dissociation of GEF-H1 from NPR-C.•Osteocrin enhanced Ser886 phosphorylation and binding to 14-3-3 of GEF-H1.•Osteocrin increased the amount of activated GEF-H1.