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Delayed transactivation of the receptor for nerve growth factor is required for sustained signaling and differentiation by alpha(2)-adrenergic receptors in transfected PC12 cells

机译:神经生长因子受体的延迟反式激活是持续的信号和转染的PC12细胞中的alpha(2)-肾上腺素受体分化所必需的。

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alpha(2)-Adrenergic receptors have been reported to induce subtype-specific neuronal differentiation in vitro, but the signaling mechanisms that mediate this effect have not been characterized. In the present study we found that stimulated alpha(2)-ARs induce delayed transactivation of TrkA in PC 12 cells. The transactivation of TrkA was sensitive to the PP I inhibitor of the Src family kinases and required prior transactivation of the EGF receptor. Moreover, alpha(2)-adrenergic receptors induced sustained activation of MAPK and Akt. The sustained activation of Akt, but not of MAPK, was subtype-specific and correlated with the neuronal differentiation of PC12 cells, with the order alpha(2A) < alpha(2B) < alpha(2C). Furthermore, stimulated alpha(2)- ARs induced an increased over time expression of the cell cycle associated proteins, p21(WAF1) and Cyclin D1 and led to cell cycle arrest in a similar subtype-specific manner. Contrary to sustained activation of MAPK, the persistent activation of Akt and of p21(WAF1) and Cyclin D1 as well as neurite outgrowth and expression of the neuronal marker peripherin, were all blocked by K252a an inhibitor of TrkA activity. Together these results demonstrate a novel outcome following alpha(2)-AR-mediated EGFR transactivation, being the consecutive transactivation of TrkA, and that this event may mediate the subtype-specific differentiation of alpha(2)-AR-expressing PC 12 cells. (c) 2006 Elsevier Inc. All rights reserved.
机译:据报道,α(2)-肾上腺素能受体在体外诱导亚型特异性神经元分化,但尚未鉴定介导此作用的信号传导机制。在本研究中,我们发现受刺激的alpha(2)-ARs在PC 12细胞中诱导TrkA的延迟反式激活。 TrkA的反式激活对Src家族激酶的PP I抑制剂敏感,需要事先对EGF受体进行反式激活。此外,α(2)-肾上腺素受体诱导MAPK和Akt的持续激活。 Akt而非MAPK的持续激活是亚型特异性的,并且与PC12细胞的神经元分化相关,顺序为alpha(2A)

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