A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy
A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy
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DOI：
10.1093/emboj/cdg637
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发表时间：
2003-12-15
期刊：
影响因子：
11.4
通讯作者：
Inagami, T
中科院分区：
文献类型：
--
作者：
Senbonmatsu, T;Saito, T;Inagami, T
我们描述了由g蛋白偶联受体（GPCR）血管紧张素II (Ang II) 2型受体（AT(2)）介导的一种新的信号传导机制。酵母双杂交研究和亲和柱结合实验表明，分离的AT(2) c端与转录因子早幼粒细胞锌指蛋白（PLZF）结合。使用共聚焦显微镜的细胞研究表明，Ang II刺激诱导细胞质PLZF与AT(2)在质膜处共定位，然后驱动AT(2)和PLZF内化。PLZF在核内缓慢出现，而AT(2)在核周区域积累。核PLZF结合磷脂酰肌醇-3激酶p85 α亚基（p85 α PI3K）基因的一致序列。AT(2)增强p85alpha PI3K的表达，随后增强p70（S6）激酶，这是蛋白质合成所必需的。PLZF的失活突变体消除了这种影响。与许多其他组织不同，PLZF在心脏中表达强烈。这种涉及AT(2)、PLZF和p85alpha PI3K的心脏选择性通路可能解释了AT(2)基因缺失小鼠心脏肥厚反应的缺失。
We describe a novel signaling mechanism mediated by the G-protein-coupled receptor (GPCR) angiotensin II (Ang II) type 2 receptor (AT(2)). Yeast two-hybrid studies and affinity column binding assay show that the isolated AT(2) C-terminus binds to the transcription factor promyelocytic zinc finger protein (PLZF). Cellular studies employing confocal microscopy show that Ang II stimulation induces cytosolic PLZF to co-localize with AT(2) at the plasma membrane, then drives AT(2) and PLZF to internalize. PLZF slowly emerges in the nucleus whereas AT(2) accumulates in the perinuclear region. Nuclear PLZF binds to a consensus sequence of the phosphatidylinositol-3 kinase p85alpha subunit (p85alpha PI3K) gene. AT(2) enhances expression of p85alpha PI3K followed by enhanced p70(S6) kinase, essential to protein synthesis. An inactive mutant of PLZF abolishes this effect. PLZF is expressed robustly in the heart in contrast to many other tissues. This cardiac selective pathway involving AT(2), PLZF and p85alpha PI3K may explain the absence of a cardiac hypertrophic response in AT(2) gene-deleted mice.