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LIF-mediated maintenance of PACAP-induced neurite outgrowths in human SH-SY5Y neuroblastoma cells require PI3K but not STAT or ERK signaling pathways

Lutz, Eve M. and Monaghan, Thomas K. and Pou, Chantevy and Plevin, Robin and MacKenzie, Christopher J. (2010) LIF-mediated maintenance of PACAP-induced neurite outgrowths in human SH-SY5Y neuroblastoma cells require PI3K but not STAT or ERK signaling pathways. Journal of Molecular Neuroscience, 42 (3). p. 297. ISSN 0895-8696

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Abstract

Previously, we have shown that pituitary adenylate cyclase-activating polypeptide (PACAP) induces neuritogenesis in human SH-SY5Y cells through a cAMP-dependent but protein kinase A-independent mechanism involving activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways. However, the morphological changes induced by PACAP are transient, with the increase in number of neurite-bearing cells peaking at day 4 before returning to control cell levels over an 8-day time course. Control cells maintain an undifferentiated neuroblast morphology during the 8-day experiment. On the other hand, neurite extensions are maintained by cells co-treated with PACAP and the neuropoietic cytokine leukemia inhibitory factor (LIF), with similar levels in the number of neurite-bearing cells observed at day 8 to that at day 4. Interestingly, the induction of neurite outgrowths in SH-SY5Y cells requires a minimal 2-h treatment with PACAP, with 4–6 h of treatment inducing similar peak levels of neurite-bearing cells observed at day 4 to that of continual PACAP treatment. LIF is not required until day 4 after which continual treatment with LIF is necessary for neurite maintenance in PACAP-treated cells. The signaling pathways activated by LIF were investigated also. LIF elicits signal transducer and activator of transcription 3 (STAT3) but not STAT1 tyrosine phosphorylation along with a transient activation of the ERK and prolonged activation of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (PKB/Akt) in PACAP-treated and control SH-SY5Y cells. Phosphorylation of serine 727 on STAT3 was detected in PACAP-treated but not control cells, and this was prevented by the MEK-1 inhibitor PD98059. Activation of p38 MAPK or c-jun N-terminal kinase (JNK) were not detected, however, an elevated basal level of phosphorylated p38 MAP kinase was observed in PACAP-treated cells. Neither PD98059 nor siRNA knockdown of STAT3 prevented LIF-mediated maintenance of PACAP-induced neurite extensions. However, the PI3K inhibitor wortmannin was found to effectively block LIF maintenance of neurite outgrowths in PACAP-treated cells. Thus, the ability of LIF to stabilize and maintain PACAP-induced neurite outgrowths requires PI3K but not the STAT3 or ERK signaling pathways in SH-SY5Y cells.