Neeli Indira, Liu Zhimin, Dronadula Nagadhara, Ma Z Alex, Rao Gadiparthi N
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
J Biol Chem. 2004 Oct 29;279(44):46122-8. doi: 10.1074/jbc.M406922200. Epub 2004 Aug 22.
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 PDGFBB-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.
血小板衍生生长因子 - BB（PDGF - BB）是血管平滑肌细胞（VSMC）的一种强效促有丝分裂原。为了解其促有丝分裂信号事件，我们研究了Janus激活激酶/信号转导子和转录激活子（Jak/STAT）途径以及胞质磷脂酶A2（cPLA2）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，AG490和Jak - 2KEpRK5（分别为Jak - 2的选择性药理抑制剂和显性负性突变体）减弱了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。Jak - 2和STAT - 3的显性负性突变体依赖性抑制阻断了PDGF - BB诱导的VSMC运动。PDGF - BB以Jak - 2/STAT - 3依赖性方式诱导cPLA2的表达，cPLA2的药理抑制剂可阻止PDGF - BB诱导的VSMC运动。此外，外源性添加花生四烯酸或cPLA2的强制表达可使PDGF - BB诱导的VSMC运动从Jak - 2和STAT - 3激活阻断的抑制中恢复。总之，这些结果首次表明PDGF - BB诱导的VSMC运动需要Jak - 2/STAT - 3/cPLA2信号轴的激活。
