Cannabinoid 1 Receptor and Interleukin-6 Receptor Together Induce Integration of Protein Kinase and Transcription Factor Signaling to Trigger Neurite Outgrowth

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2009; 285(2):1358-70. DOI: 10.1074/jbc.M109.049841
Source: PubMed


Activation of the G(o/i)-coupled cannabinoid 1 receptor (CB1R) has been shown to induce neurite outgrowth in Neuro2A cells through activation of Src kinase and STAT3 transcription factor. Signaling by the interleukin 6 receptor (IL-6R) also activates STAT3 through Jak kinase. We studied if signals from the two pathways could be integrated in a synergistic manner to trigger neurite outgrowth in Neuro2A cells. At low concentrations, when agonist at either receptor by itself has no effect, we found that CB1R and IL-6R stimulation together induced synergistic neurite outgrowth. Signal integration requires activation of transcription factors by Src, Jak, and mitogen-activated protein kinases. Mitogen-activated protein kinase can be activated by both receptors and shows enhanced early activation in the presence of both ligands. CREB and STAT3 transcription factors are required for synergy and show enhanced DNA-binding activity when both receptors are activated. STAT3 plays a critical role in integration of the signals downstream of the two receptors. When both pathways are activated, STAT3 phosphorylation is sustained for 6 h. This prolonged activation of STAT3 requires deactivation of SHP2 phosphatase. Reduction of SHP2 levels by RNA interference results in greater synergy in neurite outgrowth. Simultaneous knockdown of both SHP2 and STAT3 blocks the synergistic triggering of neurite outgrowth, indicating that STAT3 is downstream of SHP2. CB1R and IL-6R co-stimulation enhanced the differentiation of rat cortical neuron primary cultures. These results provide a mechanism where multiple protein kinases and transcription factors interact to integrate signals from G protein-coupled and cytokine receptor to evoke neurite outgrowth in Neuro2A cells.

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    • "The JAK/STAT3 pathway is activated after nerve injury in DRG and motor neurons and maintains neuronal survival and drives axon regeneration [17-23]. Phosphorylation on Tyr705 and transcriptional activation of STAT3 is modulated by cytokines, including IL-1β [2,24,25] and growth factors [26,27]. STAT3 phosphorylation on Ser727 regulates its translocation to the mitochondria and modulates the activity of electron transport Complex I [28-30]. "
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    Molecular Brain 10/2013; 6(1):45. DOI:10.1186/1756-6606-6-45 · 4.90 Impact Factor
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    • "ABHD6 mRNA levels were higher in schizophrenia subjects under 40 years of age (0.043 ± 0.001) and with illness duration of less than 15 years (0.041 ± 0.004) relative to age-matched comparison subjects (0.036 ± 0.002 and 0.036 ± 0.002, respectively) but did not differ in the other groups. disturbances in 2-AG signaling may interfere with neurite formation and dendritic maintenance in schizophrenia (Bellon, 2007; Keimpema et al., 2010; Zorina et al., 2010; Bellon et al., 2011). Furthermore, ABHD6 regulates 2-AG-mediated, CB1R-dependent long term depression of excitatory postsynaptic potentials in adult mouse prefrontal cortex (Marrs et al., 2010), suggesting that alterations in ABHD6 levels may impact glutamatergic signaling in the disorder. "
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