Heregulin-stimulated acetylcholine receptor gene expression in muscle: Requirement for MAP kinase and evidence for a parallel inhibitory pathway independent of electrical activity
Heregulin-stimulated acetylcholine receptor gene expression in muscle: Requirement for MAP kinase and evidence for a parallel inhibitory pathway independent of electrical activity
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DOI：
10.1093/emboj/16.4.717
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发表时间：
1997-02-17
期刊：
影响因子：
11.4
通讯作者：
Changeux, JP
中科院分区：
文献类型：
--
作者：
Altiok, N;Altiok, S;Changeux, JP
调蛋白（HRG）与其受体ErbB 3的结合导致与ErbB 2/neu的二聚化和其内在酪氨酸激酶的激活，启动级联反应，导致肌肉中乙酰胆碱受体（AChR）基因的刺激。在这里，我们检查了HRG受体下游的信号传导。我们发现，磷脂酰肌醇3 '-激酶（PI 3 K）和SHC结合HRG激活的ErbB 3在肌管。随后，p70 S6激酶（p70（S6 k））和MAP激酶ERK 2以及p90（rsk）被激活。然而，抑制PI 3 K和p70（S6 K）渥曼青霉素和雷帕霉素，分别未能拮抗乙酰胆碱受体α亚基基因的表达刺激HRG，尽管事实上，激酶的活性被抑制。相反，这些抑制剂升高AChR α-亚基mRNA水平，通过自己，独立的肌肉电活动。另一方面，17聚体反义寡核苷酸，EAS 1，造成了一个特定的消耗ERK 2和消除的能力，HRG刺激AChR α亚基基因的表达。这些结果表明，HRG刺激AChR基因的表达，通过ERK 2激活，并提供了一个生理的例子，神经营养因子相关的抑制AChR基因的刺激p70（S6 k）的活动，这可能有助于成人型AChR基因的表达在神经肌肉接头。
Binding of heregulin (HRG) to its receptor, ErbB3, results in a dimerization with ErbB2/neu and activation of their intrinsic tyrosine kinases, initiating a cascade of events resulting in the stimulation of acetylcholine receptor (AChR) genes in muscle. Here we have examined the signalling downstream of the HRG receptor. We show that phosphatidylinositol 3'-kinase (PI3K) and SHC bind to the HRG-activated ErbB3 in myotubes. Subsequently, p70S6 kinase (p70(S6k)), and MAP kinase ERK2 and thereby p90(rsk) are activated. However, inhibition of PI3K and p70(S6k) by wortmannin and rapamycin, respectively, failed to antagonize AChR alpha-subunit gene expression stimulated by HRG, despite the fact that the activities of the kinases were inhibited. In contrast, these inhibitors elevated AChR alpha-subunit mRNA levels, by themselves, independently of muscle electrical activity. On the other hand, the 17mer antisense oligonucleotide, EAS1, caused a specific depletion of ERK2 and eliminated the ability of HRG to stimulate AChR alpha-subunit gene expression. These results indicate that HRG stimulates expression of AChR genes via ERK2 activation, and provide a physiological example of neurotrophic factor-associated repression of AChR genes by stimulation of p70(S6k) activity which may contribute to the expression of adult type AChR genes at the neuromuscular junction.