Natriuretic peptide receptor-C releases and activates guanine nucleotide-exchange factor H1 in a ligand-dependent manner
Natriuretic peptide receptor-C releases and activates guanine nucleotide-exchange factor H1 in a ligand-dependent manner
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利钠肽受体-C 以配体依赖性方式释放并激活鸟嘌呤核苷酸交换因子 H1
DOI：
10.1016/j.bbrc.2021.03.028
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发表时间：
2021
影响因子：
3.1
通讯作者：
Keizo Yuasa
中科院分区：
文献类型：
--
作者：
Mika Nishida;Kenji Miyamoto;Shogo Abe;Maki Shimada;Yuki Shimizu;Akihiko Tsuji;Keizo Yuasa
虽然钠肽受体c （NPR-C）参与血浆中钠肽的清除，但它还具有其他生理功能，如通过g - αi抑制腺苷酸环化酶活性。然而，其生理作用和细胞内信号通路尚未完全阐明。在这项研究中，我们鉴定了一种rhoa特异性鸟嘌呤核苷酸交换因子GEF-H1，作为一种新的NPR-C结合蛋白。我们证明内源性的NPR-C在HeLa细胞中与GEF-H1相互作用，并且NPR-C和GEF-H1之间的相互作用依赖于NPR-C的37个氨基酸的细胞质区域。相反，另一种利钠肽受体NPR-A，包括细胞内区域的激酶同源性和guanyyl环化酶结构域，不与GEF-H1相互作用。我们还发现，NPR-C的配体（即ANP、CNP和骨蛋白）导致GEF-H1与NPR-C分离。此外，骨蛋白处理诱导GEF-H1 Ser-886位点磷酸化，增强GEF-H1与14-3-3的相互作用，增加GEF-H1的激活量。这些发现有力地支持了NPR-C可能通过调节GEF-H1信号参与多种生理作用。
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.