Mitogenic effect of glial cell line-derived neurotrophic factor is dependent on the activation of p70S6 kinase, but independent of the activation of ERK and up-regulation of Ret in SH-SY5Y cells

Smoothened-independent activation of hedgehog signaling by rearranged during transfection promotes neuroblastoma cell proliferation and tumor growth

“…The present study has shown that activation of GDNF/RET/AKT signaling inhibits the GSK3β activity and subsequently induces the proteolytic formation of GLI activators including GLI2-A and GLI3-F, resulting in increases in GLI activators and activation of HH signaling, thereby promotes the proliferation of NB cells and tumor growth. Our findings not only correspond to previous findings demonstrating that the synergy between PI3K/AKT and HH signaling occurs in embryonic development and HHdependent tumors, and that Igf2-AKT stabilizes full-length Gli2 through Serine 230 and in turn enhances the output of transcriptional activation by HH, but also correspond to previous observations indicating that AKT inhibits GSK3β activity in a variety of signaling pathways, such as Wnt, insulin, SHH, and mTOR pathways [35][36][37][38][39]. Since AKT is able to activate mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) and in turn promotes GSK3β-independent increases in GLI transcriptional activity and GDNF promotes mitogenic effect in SH-SY5Y cells through AKT and S6K1 signaling [40,41], in the present study, we are still unable to exclude the possibility that GDNF/RET/AKT activates HH signaling through mTOR/S6K1 pathway.…”

Retinoic acid induces functional c-Ret tyrosine kinase in human neuroblastoma

“…Previously, it was reported that RA induces Ret expression in SH-SY5Y cells, and in combination with GDNF, stimulates proliferation rather than differentiation [13]. In our study, to cease the proliferation and analyze the differentiation process more clearly, the cells were treated with GDNF under serum-free conditions after prior incubation with RA.…”

“…In SH-SY5Y cells, the GDNF receptor Ret is expressed constitutively at relatively low levels and the cells have not proved suitable for studies of GDNF-Ret signalling [13]. Previously, it was reported that RA induces Ret expression in SH-SY5Y cells, and in combination with GDNF, stimulates proliferation rather than differentiation [13].…”

“…To our knowledge, the functional properties of RA-induced Ret, however, have not yet been evaluated in these cells. In SH-SY5Y cells, Ret is expressed constitutively at rather low levels and it has proved difficult to induce neuronal differentiation of these cells by the administration of its ligands, such as GDNF [13].…”

Differentiated Dopaminergic MN9D Cells Only Partially Recapitulate the Electrophysiological Properties of Midbrain Dopaminergic Neurons

“…The most striking effect of GDNF was an apparent increase in cell number rather than process extension. In this regard, others have reported similar results showing that GDNF increased proliferation in the human neuroblastoma cell lines SH-SY5Y, BE(2)-C, and IMR-32 [Hirata andKiuchi 2003, Hansford andMarshall 2005]. Since GDNF affects various signaling pathways such as Ras/extracellular signal-regulated kinase and phosphatidylino-sitol 3-kinase/Akt pathways [Worby et al, 1996], it is possible that the signaling cascades induced by GDNF binding can inhibit ion channel activity or expression.…”