Signal transduction pathways through TRK-A and TRK-B receptors in human neuroblastoma cells

Little is known about the signal transduction pathways of TRK family recept ors in neuroblastoma (NB) cells. In this study, an NE cell line, designated MP-N-TS, was established from an adrenal tumor taken from a 2-year-old boy . This cell line expressed both TRK-A and TRK-B receptors, which is rare in a single NE cell line. Therefore, the MP-N-TS cell line was used to determ ine whether the signal transduction through these constitutive receptors is functional. Three neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5), induced tyrosine phosphorylation of panTRK, and BDNF and NT-4/5 induced tyrosine phosphoryla tion of TRK-B, Tyrosine phosphorylation of panTRK and/or TRK-B by the neuro trophins was inhibited in the presence of a tyrosine kinase inhibitor K252a . Tyrosine phosphorylation of Src homologous and collagen (Shc), extracellu lar signal-regulated kinase (ERK)-1 and ERK-2, and phospholipase C-yl (PLC- yl) was increased by the three neurotrophins and the increase was inhibited in the presence of K252a, Activation of Ras, detected as the GTP-bound for m of Res, was induced by the three neurotrophins, The neurotrophins did not modulate the expressions of TRK-A or TRK-B mRNA, but they did induce the e xpression of c-fos mRNA. Exogenous NGF induced weak neurite outgrowth, wher eas exogenous BDNF and NT-4/5 induced distinct neurite outgrowth. Exogenous BDNF and NT-4/5 increased the number of viable tells, while NGF did not. O ur results demonstrate that the signal transduction pathways through TRK-A and TRK-B in MP-N-TS cells are functional and similar, and the main downstr eam signaling pathways from the three neurotrophins are mitogen-activated p rotein kinase (MAPK) cascades through Shc, activated Ras, ERK-1 and ERK-2, and the transduction pathway through PLC-gammal. Further, BDNF and NT-4/5 i ncreased cell viability, The MP-N-TS cell line should be useful for clarify ing the TRK-A and TRK-B signaling pathways responsible for the different pr ognoses in patients with NB.