GIPC interacts with the β1-adrenergic receptor and regulates β1-adrenergic receptor-mediated ERK activation
GIPC interacts with the β1-adrenergic receptor and regulates β1-adrenergic receptor-mediated ERK activation
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DOI：
10.1074/jbc.m212352200
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发表时间：
2003-07-11
影响因子：
4.8
通讯作者：
Lefkowitz, RJ
中科院分区：
文献类型：
--
作者：
Hu, LYA;Chen, W;Lefkowitz, RJ
β（1）-肾上腺素能受体在人心脏中高水平表达，具有羧基末端ESKV基序，其可直接与含PDZ结构域的蛋白质相互作用。以β 1肾上腺素能受体羧基端为诱饵，我们在酵母双杂交筛选人心脏cDNA文库中鉴定了新的β 1肾上腺素能受体结合伴侣GIPC。在这里，我们证明，PDZ结构域的蛋白质，GIPC，共免疫沉淀与β（1）-肾上腺素能受体在COS-7细胞。这种相互作用的关键是β（1）-肾上腺素能受体羧基末端ESKV基序的Ser残基。我们的数据还表明，β（1）-肾上腺素能受体刺激激活丝裂原活化蛋白激酶，ERK 1/2。β 1肾上腺素能受体介导的ERK 1/2激活被百日咳毒素抑制，涉及G（i），并被GIPC的表达显著降低。GIPC的表达对β（1）-肾上腺素能受体螯合或受体介导的cAMP积累没有明显影响。这种GIPC效应对β（1）-肾上腺素能受体具有特异性，并依赖于完整的PDZ结合基序。这些数据表明，GIPC可以调节β（1）-肾上腺素能受体刺激的G（i）介导的ERK激活，而对受体内化或G（s）介导的cAMP信号传导没有影响。
beta(1)-adrenergic receptors, expressed at high levels in the human heart, have a carboxyl-terminal ESKV motif that can directly interact with PDZ domain-containing proteins. Using the beta(1)-adrenergic receptor carboxyl terminus as bait, we identified the novel beta(1)-adrenergic receptor-binding partner GIPC in a yeast two-hybrid screen of a human heart cDNA library. Here we demonstrate that the PDZ domain-containing protein, GIPC, co-immunoprecipitates with the beta(1)-adrenergic receptor in COS-7 cells. Essential for this interaction is the Ser residue of the beta(1)-adrenergic receptor carboxyl-terminal ESKV motif. Our data also demonstrate that beta(1)-adrenergic receptor stimulation activates the mitogen-activated protein kinase, ERK1/2. beta(1)-adrenergic receptor-mediated ERK1/2 activation was inhibited by pertussis toxin, implicating G(i), and was substantially decreased by the expression of GIPC. Expression of GIPC had no observable effect on beta(1)-adrenergic receptor sequestration or receptor-mediated cAMP accumulation. This GIPC effect was specific for the beta(1)-adrenergic receptor and was dependent on an intact PDZ binding motif. These data suggest that GIPC can regulate beta(1)-adrenergic receptor-stimulated, G(i)-mediated, ERK activation while having no effect on receptor internalization or G(s)-mediated cAMP signaling.