Rapid estrogenic regulation of extracellular signal-regulated kinase 1/2 signaling in cerebellar granule cells involves a G protein- and protein kinase A-dependent mechanism and intracellular activation of protein phosphatase 2A
Rapid estrogenic regulation of extracellular signal-regulated kinase 1/2 signaling in cerebellar granule cells involves a G protein- and protein kinase A-dependent mechanism and intracellular activation of protein phosphatase 2A
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DOI：
10.1210/en.2005-0564
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发表时间：
2005-12-01
期刊：
影响因子：
4.8
通讯作者：
Wong, JK
中科院分区：
文献类型：
--
作者：
Belcher, SM;Le, HH;Wong, JK
在新生大鼠小脑神经元中，17 β-雌二醇（E-2）通过膜相关受体快速刺激ERK 1/2磷酸化。本文对原代培养的颗粒细胞中E-2快速诱导ERK 1/2信号转导的机制进行了更详细的研究。这些研究的结果表明，E-2和ICI 182，780，一种雌激素受体反式激活的甾体拮抗剂，迅速增加ERK信号传导，其时间过程类似于表皮生长因子（EGF）诱导的瞬时激活。然而，表皮生长因子受体（EGFR）的自身磷酸化并没有增加E-2，和EGFR酪氨酸激酶活性的封锁并没有废除E-2的快速行动。Src-酪氨酸激酶活性的参与被证明是通过检测响应于E-2的c-Src磷酸化的增加和通过抑制Src-家族酪氨酸激酶活性来阻断E-2诱导的ERK 1/2活化。G α 1信号传导或蛋白激酶A（PKA）活性的抑制阻断了ICI 182，780快速刺激ERK信号传导的能力。在这些条件下，E-2处理诱导了基础ERK 1/2磷酸化的快速和短暂的抑制。蛋白磷酸酶2A（PP 2A）的活性迅速增加E-2，但不是由E-2共价连接到BSA。快速E-2诱导的PP 2A活性增加对百日咳毒素不敏感。目前的证据表明，在小脑颗粒细胞的ERK信号的雌激素的快速影响是通过一种新的G蛋白偶联受体机制，需要PKA和Src激酶活性连接E-2的ERK/MAPK信号模块诱导。沿着刺激ERK信号传导，E-2通过独立的信号传导机制快速激活PP 2A，该信号传导机制可作为信号持续时间的细胞特异性调节剂。
In neonatal rat cerebellar neurons, 17 beta-estradiol (E-2) rapidly stimulates ERK1/2 phosphorylation through a membrane-associated receptor. Here the mechanism of rapid E-2-induced ERK1/2 signaling in primary cultured granule cells was investigated in more detail. The results of these studies show that E-2 and ICI182,780, a steroidal antagonist of estrogen receptor transactivation, rapidly increased ERK signaling with a time course similar to the transient activation induced by epidermal growth factor (EGF). However, EGF receptor (EGFR) autophosphorylation was not increased by E-2, and blockade of EGFR tyrosine kinase activity did not abrogate the rapid actions of E-2. The involvement of Src-tyrosine kinase activity was demonstrated by detection of increased c-Src phosphorylation in response to E-2 and by blockade of E-2-induced ERK1/2 activation by inhibition of Src-family tyrosine kinase activity. Inhibition of G alpha i signaling or protein kinase A (PKA) activity blocked the ability of ICI182,780 to rapidly stimulate ERK signaling. Under those conditions, E-2 treatment induced a rapid and transient suppression of basal ERK1/2 phosphorylation. Protein phosphatase 2A (PP2A) activity was rapidly increased by E-2 but not by E-2 covalently linked to BSA. Rapid E-2-induced increases in PP2A activity were insensitive to pertussis toxin. The presented evidence indicates that the rapid effects of estrogens on ERK signaling in cerebellar granule cells are induced through a novel G protein-coupled receptor mechanism that requires PKA and Src-kinase activity to link E-2 to the ERK/MAPK signaling module. Along with stimulating ERK signaling, E-2 rapidly activates PP2A via an independent signaling mechanism that may serve as a cell-specific regulator of signal duration.