Ng Yu Pong, Cheung Zelda H, Ip Nancy Y
Department of Biochemistry, Biotechnology Research Institute, and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
J Biol Chem. 2006 Jun 9;281(23):15636-44. doi: 10.1074/jbc.M601863200. Epub 2006 Apr 11.
Signal transducer and activator of transcription 3 (STAT3) has long been shown to regulate gene transcription in response to cytokines and growth factors. Recent evidence suggests that STAT3 activation may also occur downstream of receptor-tyrosine kinase activation. In the current study we have identified STAT3 as a novel signal transducer for TrkA, the receptor-tyrosine kinase that mediates the functions of nerve growth factor (NGF). Activation of TrkA by NGF triggered STAT3 phosphorylation at Ser-727, and enhanced the DNA binding and transcriptional activities of STAT3. More importantly, neurotrophin-induced increase in STAT3 activation was observed to underlie several downstream functions of neurotrophin signaling. First of all, knockdown of STAT3 expression using the RNA interference approach attenuated NGF-induced transcription of immediate early genes in PC12 cells. Furthermore, reduced STAT3 expression in PC12 cells suppressed NGF-induced cyclin D1 expression, thereby inhibiting growth arrest normally triggered by NGF treatment. Finally, inhibition of STAT3 expression decreased brain-derived neurotrophic factor-promoted neurite outgrowth in primary hippocampal neurons. Together, our findings have identified STAT3 as an essential component of neurotrophin signaling and functions.
长期以来，转录信号转导子和激活子3（STAT3）被证明可响应细胞因子和生长因子来调节基因转录。最近有证据表明，STAT3激活也可能发生在受体酪氨酸激酶激活的下游。在本研究中，我们已确定STAT3是TrkA的一种新型信号转导子，TrkA是介导神经生长因子（NGF）功能的受体酪氨酸激酶。NGF激活TrkA会触发STAT3在Ser-727位点的磷酸化，并增强STAT3的DNA结合和转录活性。更重要的是，观察到神经营养因子诱导的STAT3激活增加是神经营养因子信号传导的几个下游功能的基础。首先，使用RNA干扰方法敲低STAT3表达会减弱PC12细胞中NGF诱导的即刻早期基因转录。此外，PC12细胞中STAT3表达的降低会抑制NGF诱导的细胞周期蛋白D1表达，从而抑制通常由NGF处理触发的生长停滞。最后，抑制STAT3表达会减少原代海马神经元中脑源性神经营养因子促进的神经突生长。总之，我们的研究结果已确定STAT3是神经营养因子信号传导和功能的重要组成部分。
