Sphingomyelin-derived lipids differentially regulate the extracellular signal-regulated kinase 2 (ERK-2) and c-Jun N-terminal kinase (JNK) signal cascades in airway smooth muscle
Sphingomyelin-derived lipids differentially regulate the extracellular signal-regulated kinase 2 (ERK-2) and c-Jun N-terminal kinase (JNK) signal cascades in airway smooth muscle
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DOI：
10.1111/j.1432-1033.1996.0819p.x
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发表时间：
1996-05-01
期刊：
影响因子：
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通讯作者：
Pyne, NJ
中科院分区：
文献类型：
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作者：
Pyne, S;Chapman, J;Pyne, NJ
在ASM细胞中，血小板衍生生长因子刺激快速瞬时神经鞘氨醇磷酸形成，激活细胞外信号调节激酶2(ERK-2)，磷酸化p70(S6K)，并使DNA合成增加九倍。相反，这种生长因子不能激活c-jun氨基末端激酶(JNK)。基于这些发现，我们通过评估神经鞘磷脂对ERK-2、JNK和p70(S6K)的影响来测试它们是否在生长因子信号转导中发挥作用。我们证明了神经鞘磷脂诱导ERK-2激活，对JNK无效，也不能诱导p70(S6K)的磷酸化。后者可能解释了为什么当它直接加入ASM细胞时，它是一个很差的有丝分裂原。相反，鞘氨醇和细胞通透性神经酰胺可诱导JNK明显的酪氨酸磷酸化和激活，对ERK-2的刺激作用较差，不能诱导p70(S6K)的磷酸化。因此，通过ERK-2或JNK级联传递信号的特异性可能取决于这些鞘磷脂衍生的脂类之间依赖激动剂的快速相互转换。这也可能提供一种动态机制，使生长因子和细胞因子能够引发多效性细胞反应，如增殖和细胞存活。例如，神经酰胺和鞘氨醇都将通过激活JNK而导致生长停滞，而神经鞘氨醇磷酸将增强生长因子刺激的DNA合成，这是ERK-2激活的结果。此外，在某些条件下，鞘氨醇和神经酰胺刺激cAMP的形成，cAMP是细胞生长的负调控因子，而鞘氨醇磷酸抑制cAMP，从而增强其自身的促生长特性。从这些研究中，很明显，鞘氨醇磷酸表现出与其一致的信号特征，介导了部分血小板衍生生长因子的作用。
In ASM cells platelet-derived growth factor stimulates rapid transient sphingosine phosphate formation, the activation of extracellular signal-regulated kinase 2 (ERK-2), the phosphorylation of p70(S6K), and a ninefold increase in DNA synthesis. In contrast, this growth factor fails to activate c-Jun N-terminal kinase (JNK). Based upon these findings, we have tested whether the sphingomyelin-derived sphingolipids play a role in growth factor signalling by assessing their effect on ERK-2, JNK, and p70(S6K).We demonstrate that sphingosine phosphate induces the activation of ERK-2, is ineffective against JNK, and fails to induce the phosphorylation of p70(S6K). The latter may explain why it is a poor mitogen when added directly to ASM cells. In contrast, sphingosine and cell-permeable ceramides elicit the prominent tyrosyl phosphorylation and activation of JNK, are poor stimulators of ERK-2, and do not induce the phosphorylation of p70(S6K). Therefore, the specificity of signalling through either ERK-2 or JNK cascades may be determined by the rapid agonist-dependent interconversion of these sphingomyelin-derived lipids. This may also provide a dynamic mechanism that enables growth factors and cytokines to elicit pleiotropic cell responses, such as proliferation and cell survival. For instance, both ceramide and sphingosine will elicit growth arrest via activation of JNK, whereas sphingosine phosphate will potentiate growth factor-stimulated DNA synthesis, a consequence of the activation of ERK-2. Furthermore, under certain conditions, sphingosine and ceramide stimulate cAMP formation, a negative modulator of cell growth, whereas sphingosine phosphate depresses cAMP, thereby enhancing its own growth-promoting properties.From these studies, it is evident that sphingosine phosphate displays a signalling profile that is consistent with it mediating part of the action of platelet-derived growth factor.