Abstract
BackgroundSignal 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 tyrosine705 with or without the concomitant phosphorylation at serine727, 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 serine727 (P-Ser-STAT3) in neurite outgrowth and the underlying mechanism is largely unknown.Principal FindingsIn 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 serine727 but not tyrosine705 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).ConclusionTaken 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.
Highlights
The transcription regulator Signal transducer and activator of transcription 3 (STAT3) mediates a myriad of biological functions from immune response to cell proliferation and differentiation [1,2,3]
Taken together, the findings demonstrated a hitherto unrecognized novel transcription independent mechanism whereby the mitochondria localized P-Ser-STAT3 is involved in nerve growth factor (NGF) induced neurite outgrowth
To gain insights into the involvement of STAT3 in this process, the phosphorylation state of STAT3 was investigated upon NGF stimulation
Summary
The transcription regulator STAT3 mediates a myriad of biological functions from immune response to cell proliferation and differentiation [1,2,3]. It is critically involved in the development of the rodent central nervous system [4,5,6] and plays key roles in mediating the protective and regenerative effects of cytokines, growth factors, and hormones following injuries to brain, spinal cord and peripheral nerves [3]. Adequate neurite initiation and outgrowth are essential pre-requisites to target innervation and formation of neuronal circuitry This process is typically triggered by extracellular cues and regulated through a myriad of interactive signaling pathways. The involvement of STAT3 mono-phosphorylated at residue serine727 (P-Ser-STAT3) in neurite outgrowth and the underlying mechanism is largely unknown
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