Interferon-β alters neurotrophin-3 TrkC receptor expression and signaling in differentiated human SH-SY5Y neuroblastoma cells

Both type I interferons (IFNs) and neurotrophins act on neuronal cells to regulate survival, growth and differentiation. However, relatively little is known on the interaction between these two classes of regulatory proteins. We have previously reported that IFN-β causes down-regulation of the brain-derived neurotrophic factor/TrkB receptor function and up-regulation of the nerve growth factor/TrkA/p75 receptor complex. In the present study, we investigated the effects of long-term exposure to IFN-β on the functional activity of the neurotrophin 3 (NT3)/TrkC receptor system in differentiated SH-SY5Y human neuroblastoma cells. We found that IFN-β treatment curtailed NT3-induced activation of distinct signaling molecules regulated by TrkC receptor, including protein kinase B/Akt, phospholipase Cγ1 and extracellular signal-regulated kinase 1 and 2. Analysis of TrkC receptor expression showed the presence of both 140 kDa full-length and 90-100 kDa kinase-deficient truncated isoforms. Exposure to IFN-β induced a predominant enhancement in the levels of the truncated TrkC receptor isoform in a time-dependent fashion. As the main function of the truncated receptor is the inhibition of the kinase-active TrkC receptor isoforms, our data suggest that long-term exposure to IFN-β down-regulates NT3 signaling by altering the balance between kinase-active and inactive TrkC receptor isoforms.