Department of Biochemistry, National University of Singapore, Singapore, Singapore.
PLoS One. 2011;6(6):e21680. doi: 10.1371/journal.pone.0021680. Epub 2011 Jun 27.
Signal transducer and activator of transcription 3 (STAT3) plays critical roles in neural development and is increasingly recognized as a major mediator of injury response in the nervous system. Cytokines and growth factors are known to phosphorylate STAT3 at tyrosine(705) with or without the concomitant phosphorylation at serine(727), resulting in the nuclear localization of STAT3 and subsequent transcriptional activation of genes. Recent evidence suggests that STAT3 may control cell function via alternative mechanisms independent of its transcriptional activity. Currently, the involvement of STAT3 mono-phosphorylated at residue serine(727) (P-Ser-STAT3) in neurite outgrowth and the underlying mechanism is largely unknown.
In this study, we investigated the role of nerve growth factor (NGF) induced P-Ser-STAT3 in mediating neurite outgrowth. NGF induced the phosphorylation of residue serine(727) but not tyrosine(705) of STAT3 in PC12 and primary cortical neuronal cells. In PC12 cells, serine but not tyrosine dominant negative mutant of STAT3 was found to impair NGF induced neurite outgrowth. Unexpectedly, NGF induced P-Ser-STAT3 was localized to the mitochondria but not in the nucleus. Mitochondrial STAT3 was further found to be intimately involved in NGF induced neurite outgrowth and the production of reactive oxygen species (ROS).
Taken together, the findings herein demonstrated a hitherto unrecognized novel transcription independent mechanism whereby the mitochondria localized P-Ser-STAT3 is involved in NGF induced neurite outgrowth.
信号转导子和转录激活子 3（STAT3）在神经发育中起着关键作用，并且越来越被认为是神经系统损伤反应的主要介质。众所周知，细胞因子和生长因子可使 STAT3 在酪氨酸（705）处磷酸化，而无需同时在丝氨酸（727）处磷酸化，从而导致 STAT3 的核定位以及随后的基因转录激活。最近的证据表明，STAT3 可能通过与其转录活性无关的替代机制来控制细胞功能。目前，丝氨酸残基（727）单磷酸化的 STAT3（P-Ser-STAT3）在轴突生长中的作用及其潜在机制在很大程度上尚不清楚。
在这项研究中，我们研究了神经生长因子（NGF）诱导的 P-Ser-STAT3 在介导轴突生长中的作用。NGF 诱导 PC12 和原代皮质神经元细胞中 STAT3 的丝氨酸（727）残基磷酸化，但不诱导酪氨酸（705）残基磷酸化。在 PC12 细胞中，发现丝氨酸而非酪氨酸显性负 STAT3 突变体可损害 NGF 诱导的轴突生长。出乎意料的是，NGF 诱导的 P-Ser-STAT3 定位于线粒体而不是细胞核。进一步发现线粒体 STAT3 密切参与 NGF 诱导的轴突生长和活性氧（ROS）的产生。
总之，这些发现证明了一种以前未知的新的转录非依赖性机制，其中定位于线粒体的 P-Ser-STAT3 参与 NGF 诱导的轴突生长。
