An essential role of the Jak-2/STAT-3/cytosolic phospholipase A2 axis in platelet-derived growth factor BB-induced vascular smooth muscle cell motility
An essential role of the Jak-2/STAT-3/cytosolic phospholipase A2 axis in platelet-derived growth factor BB-induced vascular smooth muscle cell motility
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DOI：
10.1074/jbc.m406922200
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发表时间：
2004-10-29
影响因子：
4.8
通讯作者：
Rao, GN
中科院分区：
文献类型：
--
作者：
Neeli, I;Liu, ZM;Rao, GN
血小板源性生长因子-BB（PDGF-BB）是血管平滑肌细胞（VSMCs）的一种强有力的运动原。为了了解其运动信号事件，我们研究了Janus激活的激酶/信号转导和转录激活因子（Jak/STAT）途径和胞浆磷脂酶A（2）（cPLA（2））的作用。PDGF-BB以时间依赖性方式刺激VSMC中Jak-2和STAT-3的酪氨酸磷酸化。此外，AG 490和Jak-2KEPRK 5，分别是Jak-2的选择性药理学抑制剂和显性负突变体，减弱PDGF-BB诱导的STAT-3酪氨酸磷酸化及其DNA结合和报告基因活性。PDGF-BB以剂量依赖性方式诱导VSMC运动，在10 ng/ml时具有最大效应。显性负性muplatin依赖性抑制Jak-2和STAT-3阻断PDGF-BB诱导的VSMC运动。PDGF-BB以Jak-2/STAT-3依赖的方式诱导cPLA（2）的表达，cPLA（2）的药理学抑制剂阻止PDGF-BB诱导的VSMC运动。此外，外源性添加花生四烯酸或强制表达cPLA（2）可通过阻断Jak-2和STAT-3激活来挽救PDGF-BB诱导的VSMC运动抑制。总之，这些结果首次表明PDGF-BB诱导的VSMC运动需要激活Jak-2/STAT-3/cPLA（2）信号轴。
Platelet-derived growth factor-BB (PDGF-BB) is a potent motogen for vascular smooth muscle cells (VSMCs). To understand its motogenic signaling events, we have studied the role of the Janus-activated kinase/signal transducers and activators of transcription (Jak/STAT) pathway and cytosolic phospholipase A(2) (cPLA(2)). PDGF-BB stimulated tyrosine phosphorylation of Jak-2 and STAT-3 in a time-dependent manner in VSMCs. In addition, AG490 and Jak-2KEpRK5, a selective pharmacological inhibitor and a dominant negative mutant, respectively, of Jak-2, attenuated PDGF-BB-induced STAT-3 tyrosine phosphorylation and its DNA binding and reporter gene activities. PDGF-BB induced VSMC motility in a dose-dependent manner with a maximum effect at 10 ng/ml. Dominant negative mutant-dependent suppression of Jak-2 and STAT-3 blocked PDGF-BB-induced VSMC motility. PDGF-BB induced the expression of cPLA(2) in a Jak-2/STAT-3-dependent manner, and pharmacological inhibitors of cPLA(2) prevented PDGF-BB-induced VSMC motility. Furthermore, either exogenous addition of arachidonic acid or forced expression of cPLA(2) rescued PDGF-BB-induced VSMC motility from inhibition by blockade of Jak-2 and STAT-3 activation. Together, these results for the first time show that PDGF-BB-induced VSMC motility requires activation of the Jak-2/STAT-3/cPLA(2) signaling axis.