CCM2 and PAK4 act downstream of atrial natriuretic peptide signaling to promote cell spreading.
CCM2 and PAK4 act downstream of atrial natriuretic peptide signaling to promote cell spreading.
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CCM2 和 PAK4 作用于心房钠尿肽信号传导下游，促进细胞扩散。
DOI：
10.1042/bcj20160841
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Kangawa K.
中科院分区：
文献类型：
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作者：
Miura K;Nojiri T;Akitake Y;Ando K;Fukuhara S;Zenitani M;Kimura T;Hino J;Miyazato M;Hosoda H;Kangawa K.
心房利钠肽（ANP）是一种心脏激素，由心房释放，以响应拉伸力。ANP通过其受体鸟苷酸环化酶-A（GC-A），通过发挥利尿、利钠和利尿作用（部分由内皮细胞介导）维持心血管稳态。在体内和体外，ANP通过降低RhoA活性和重组肌动蛋白细胞骨架来增强内皮屏障功能。我们建立了稳定表达GC-A的小鼠内皮细胞，并用它们来分析肌动蛋白重组的分子机制。ANP刺激导致肌球蛋白轻链（MLC）磷酸化，促进细胞铺展。p21激活激酶4（PAK 4）和脑海绵状血管畸形2（CCM 2）是参与脑血管疾病的支架蛋白，它们是MLC磷酸化和ANP促进细胞扩散所必需的。最后，除了GC结构域之外，GC-A的激酶同源结构域也是ANP/GC-A信号传导所必需的。我们的研究结果表明，CCM 2和PAK 4是参与细胞扩散的ANP/GC-A信号传导的重要下游介质，这是增强内皮屏障功能的重要初始步骤。
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. Bothin vivoandin 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.