title: Suppressor of cytokine signalling-6 promotes neurite outgrowth via JAK2/STAT5-mediated signalling pathway, involving negative feedback inhibition.
abstract: BACKGROUND
  Suppressors of cytokine signalling (SOCS) protein family are key regulators of cellular responses to cytokines and play an important role in the nervous system. The SOCS6 protein, a less extensively studied SOCS family member, has been shown to induce insulin resistance in the retina and promote survival of the retinal neurons. But no reports are available about the role of SOCS6 in neuritogenesis. In this study, we examined the role of SOCS6 in neurite outgrowth and neuronal cell signalling.
  
  
  RESULTS
  The effect of SOCS6 in neural stem cells differentiation was studied in neural stem cells and PC12 cell line. Highly elevated levels of SOCS6 were found upon neural cell differentiation both at the mRNA and protein level. Furthermore, SOCS6 over-expression lead to increase in neurite outgrowth and degree of branching, whereas SOCS6 knockdown with specific siRNAs, lead to a significant decrease in neurite initiation and extension. Insulin-like growth factor-1 (IGF-1) stimulation which enhanced neurite outgrowth of neural cells resulted in further enhancement of SOCS6 expression. Jak/Stat (Janus Kinase/Signal Transducer And Activator Of Transcription) pathway was found to be involved in the SOCS6 mediated neurite outgrowth. Bioinformatics study revealed presence of putative Stat binding sites in the SOCS6 promoter region. Transcription factors Stat5a and Stat5b were involved in SOCS6 gene upregulation leading to neuronal differentiation. Following differentiation, SOCS6 was found to form a ternary complex with IGFR (Insulin Like Growth Factor-1 Receptor) and JAK2 which acted in a negative feedback loop to inhibit pStat5 activation.
  
  
  CONCLUSIONS
  The current paradigm for the first time states that SOCS6, a SOCS family member, plays an important role in the process of neuronal differentiation. These findings define a novel molecular mechanism for Jak2/Stat5 mediated SOCS6 signalling.
authors: Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi, India.
authors: Sakshi
authors: S
authors: Gupta
authors: Kanchan
authors: K
authors: Mishra
authors: Avadhesha
authors: A
authors: Surolia
authors: Kakoli
authors: K
authors: Banerjee
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016716:PC12 Cells; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C571066:SOCS6 protein, rat; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D007334:Insulin-Like Growth Factor I; C507927:Jak2 protein, rat; D053614:Janus Kinase 2