• Open Access

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 receptors in neuroblastoma (NB) cells. In this study, an NB 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 NB cell line. Therefore, the MP-N-TS cell line was used to determine 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 phosphorylation of TRK-B. Tyrosine phosphorylation of panTRK and/or TRK-B by the neurotro-phins was inhibited in the presence of a tyrosine kinase inhibitor K252a. Tyrosine phosphorylation of Src homologous and collagen (She), extracellular signal-regulated kinase (ERK)-l and ERK-2, and phospholipase C-γl (PLC-γl) was increased by the three neurotrophins and the increase was inhibited in the presence of K252a. Activation of Ras, detected as the GTP-bound form of Ras, 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 expression of c-fos mRNA. Exogenous NGF induced weak neurite outgrowth, whereas exogenous BDNF and NT-4/5 induced distinct neurite outgrowth. Exogenous BDNF and NT-4/5 increased the number of viable cells, while NGF did not. Our 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 downstream signaling pathways from the three neurotrophins are mitogen-activated protein kinase (MAPK) cascades through She, activated Ras, ERK-1 and ERK-2, and the transduction pathway through PLC-γl. Further, BDNF and NT-4/5 increased cell viability. The MP-N-TS cell line should be useful for clarifying the TRK-A and TRK-B signaling pathways responsible for the different prognoses in patients with NB.