Opposing roles of PKA and EPAC in the cAMP-dependent regulation of schwann cell proliferation and differentiation [corrected].
Opposing roles of PKA and EPAC in the cAMP-dependent regulation of schwann cell proliferation and differentiation [corrected].
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DOI：
10.1371/journal.pone.0082354
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Monje PV
中科院分区：
文献类型：
--
作者：
Bacallao K;Monje PV
在雪旺细胞（SC）中，环磷酸腺苷（cAMP）不仅诱导分化成髓鞘形成SC相关表型，而且协同增强生长因子如神经调节蛋白的促有丝分裂作用。为了更好地理解cAMP发挥这些明显矛盾的功能的分子机制，我们研究了cAMP的两个主要效应物蛋白激酶A（PKA）和cAMP激活的交换蛋白（EPAC）对分离的和轴突相关的SC的增殖和分化的作用。对于这些研究，使用了各种PKA和EPAC激动剂和拮抗剂，包括cAMP的途径选择性类似物和药理学抑制剂。我们的研究表明，PKA的活性，而不是EPAC的活性所需的cAMP对S期进入的辅助作用，而EPAC的活性，而不是PKA的需要SC分化和髓鞘形成。尽管选择性EPAC激活在SC中具有整体抗增殖作用，但它未能驱动Krox-20（髓鞘形成的主要调节剂）以及髓鞘特异性蛋白质和脂质的表达，这表明EPAC激活不足以驱动完全分化反应。有趣的是，EPAC活性的抑制导致SC分化和髓鞘形成的严重损害，但不是Krox-20的表达，这表明Krox-20调节响应cAMP的独立机制。总之，我们的数据支持的想法，cAMP信号转导的结果取决于特定的一组效应激活的SC。cAMP的促有丝分裂作用完全依赖于PKA活性，而cAMP的分化作用需要部分由EPAC转导的PKA非依赖性（非经典）cAMP特异性途径。
In Schwann cells (SCs), cyclic adenosine monophosphate (cAMP) not only induces differentiation into a myelinating SC-related phenotype, but also synergistically enhances the mitogenic action of growth factors such as neuregulin. To better understand the molecular mechanism by which cAMP exerts these apparently contradictory functions, we investigated the role of the two main effectors of cAMP, protein kinase A (PKA) and the exchange protein activated by cAMP (EPAC), on the proliferation and differentiation of both isolated and axon-related SCs. For these studies, a variety of PKA and EPAC agonists and antagonists were used, including pathway-selective analogs of cAMP and pharmacological inhibitors. Our studies indicated that the activity of PKA rather than EPAC was required for the adjuvant effect of cAMP on S-phase entry, whereas the activity of EPAC rather than PKA was required for SC differentiation and myelin formation. Even though selective EPAC activation had an overall anti-proliferative effect in SCs, it failed to drive the expression of Krox-20, a master regulator of myelination, and that of myelin-specific proteins and lipids, suggesting that EPAC activation was insufficient to drive a full differentiating response. Interestingly, inhibition of EPAC activity resulted in a drastic impairment of SC differentiation and myelin formation but not Krox-20 expression, which indicates an independent mechanism of Krox-20 regulation in response to cAMP. In conclusion, our data supports the idea that the outcome of cAMP signaling in SCs depends on the particular set of effectors activated. Whereas the mitogenic action of cAMP relies exclusively on PKA activity, the differentiating action of cAMP requires a PKA-independent (non-canonical) cAMP-specific pathway that is partially transduced by EPAC.
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依赖CAMP依赖性蛋白激酶A途径在产后雪旺氏细胞中的E-钙粘蛋白表达受到调节。
影响因子：
6.2
作者：
Crawford, Audrita T.;Desai, Darshan;Gokina, Pradeepa;Basak, Sayantani;Kim, Haesun A.
通讯作者：
Kim, Haesun A.
影响因子：
6.2
作者：
Birchmeier, Carmen;Nave, Klaus-Armin
通讯作者：
Nave, Klaus-Armin
影响因子：
4
作者：
Leitman, Ellen M.;Tewari, Ambika;Melendez-Vasquez, Carmen V.
通讯作者：
Melendez-Vasquez, Carmen V.
影响因子：
6.2
作者：
Monje, Paula V.;Rendon, Sayuri;Athauda, Gagani;Bates, Margaret;Wood, Patrick M.;Bunge, Mary Bartlett
通讯作者：
Bunge, Mary Bartlett
影响因子：
3.3
作者：
Kiermayer, S;Biondi, RM;Piiper, A
通讯作者：
Piiper, A