Cross-talk between androgen receptor/filamin A and TrkA regulates neurite outgrowth in PC12 cells.
Cross-talk between androgen receptor/filamin A and TrkA regulates neurite outgrowth in PC12 cells.
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DOI：
10.1091/mbc.e14-09-1352
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发表时间：
2015-08-01
影响因子：
3.3
通讯作者：
Castoria G
中科院分区：
文献类型：
--
作者：
Di Donato M;Bilancio A;D'Amato L;Claudiani P;Oliviero MA;Barone MV;Auricchio A;Appella E;Migliaccio A;Auricchio F;Castoria G
雄激素通过内源性雄激素受体（AR）的非转录作用刺激PC 12细胞的神经元分化。AR也是NGF诱导的PC 12神经突发生所必需的。雄激素或NGF触发AR与细丝蛋白和TrkA的关联，TrkA与PI 3-K δ的相互作用，以及PI 3-K δ和Rac的激活。在生理和病理条件下，类固醇和生长因子通过其受体控制神经元发育。我们发现，PC 12细胞携带内源性雄激素受体（AR），其抑制或沉默强烈干扰神经突刺激的nonaromatizable合成雄激素R1881或NGF。这意味着AR不仅在雄激素信号传导中起作用，而且在NGF信号传导中也起作用。反过来，药理学TrkA抑制剂干扰NGF或雄激素诱导的轴突发生。此外，在PC 12细胞中，雄激素或NGF触发AR与TrkA的关联、TrkA与PI 3-K δ的相互作用以及PI 3-K δ和Rac的下游活化。一旦与AR相关，细丝蛋白A（FlnA）有助于雄激素或NGF神经突发生，可能是通过其与信号传导效应物（如Rac）的相互作用。因此，本研究确定了先前未被识别的AR和TrkA之间的相互串扰，其由β1整联蛋白控制。FlnA/AR复合物和PI 3-K δ对雄激素和NGF诱导的神经元分化的作用也是新的。这是第一次在PC 12细胞中描述AR功能。
Androgens stimulate neuronal differentiation of PC12 cells by nontranscriptional action of the endogenous androgen receptor (AR). AR is also required for NGF-induced neuritogenesis of PC12. Androgens or NGF trigger AR association with filamin and TrkA, TrkA interaction with PI3-K δ, and activation of PI3-K δ and Rac. Steroids and growth factors control neuronal development through their receptors under physiological and pathological conditions. We show that PC12 cells harbor endogenous androgen receptor (AR), whose inhibition or silencing strongly interferes with neuritogenesis stimulated by the nonaromatizable synthetic androgen R1881 or NGF. This implies a role for AR not only in androgen signaling, but also in NGF signaling. In turn, a pharmacological TrkA inhibitor interferes with NGF- or androgen-induced neuritogenesis. In addition, androgen or NGF triggers AR association with TrkA, TrkA interaction with PI3-K δ, and downstream activation of PI3-K δ and Rac in PC12 cells. Once associated with AR, filamin A (FlnA) contributes to androgen or NGF neuritogenesis, likely through its interaction with signaling effectors, such as Rac. This study thus identifies a previously unrecognized reciprocal cross-talk between AR and TrkA, which is controlled by β1 integrin. The contribution of FlnA/AR complex and PI3-K δ to neuronal differentiation by androgens and NGF is also novel. This is the first description of AR function in PC12 cells.