Insulin-like Growth Factor-I-Dependent Signal Transduction Pathways Leading to the Induction of Cell Growth and Differentiation of Human Neuroblastoma Cell Line SH-SY5Y. The Roles of MAP Kinase Pathway and PI 3-Kinase Pathway.

Abstract

Abstract.IGF-I regulates cell growth, differentiation, and survival in many cultured nerve cell lines. The present study was undertaken in the human neuroblastoma cell line, SH-SY5Y, to elucidate whether there are differences in the IGF-dependent signal transduction pathways that stimulate proliferation compared to those that induce differentiation.Quiescent SH-SY5Y cells were treated with IGF-I in the presence or absence of PD98059 (an inhibitor of MEK, a MAP kinase kinase) or LY294002 (an inhibitor of PI 3-kinase).Cell growth was assessed by measuring [3H]thymidine incorporation into DNA and cell number. Cell differentiation was assessed by measuring mRNA levels of NPY and neurite outgrowth.IGF-I both induced cell proliferation and differentiation. It stimulated tyrosine phosphorylation of the type I IGF receptor (IGF-IR) 9-subunit, IRS-1, IRS-2, and Shc, and these changes were associated with activation of Erk and Akt. PD98059 inhibited activation of Erk and LY294002 repressed activation of Akt in response to IGF-I, but did not affect tyrosine phosphorylation of the IGF-IR, IRS-1, IRS-2, or Shc. Each PD98059 and LY294002 inhibited IGF-I-dependent cell proliferation in a concentration-dependent manner.In contrast, each of these inhibitors only partially depressed NPY gene expression induced by IGF-I and slightly inhibited IGF-I-mediated neurite outgrowth; however, when both PD98059 and LY294002 were present, IGF-I-dependent NPY gene expression and neurite outgrowth were abolished completely.These results suggest that in these nerve cells, 1) the IGF-I signals through the MAP kinase pathway and PI-3 kinase pathway are independently essential to induce IGF-I-dependent growth, and 2) alternate activation of the MAP kinase pathway and PI 3-kinase pathway is sufficient for the cells to undergo IGF-I-dependent differentiation.

Insulin-like growth factor-I signaling in human neuroblastoma cells

“…Results from the current study suggest that IGF-I activation of both Insulin-like growth factor-I signaling in neuroblastoma B Kim et al PI 3-K and MAPK pathways is needed for IGF-Imediated neurite outgrowth in N cells. In agreement with our results, Kurihara et al (2000) reported that inhibition of either MAPK or PI 3-K pathways results in decreased neurite outgrowth, while Sarbassov and Peterson (1998) found that PI 3-K is required for the prolonged activation of MAPK in myogenic differentiation.…”

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

“…Next, we tested candidate growth factors as potential regulators of MAPK pathway activity in progenitor cells. Our attention centered on IGF-1 since it has been shown to both regulate the MAPK cascade and increase the rate of progenitor cell proliferation in the dentate gyrus (Aberg et al, 2000(Aberg et al, , 2003Kurihara et al, 2000). Initially, we examined the expression pattern of IGF-1 in the dentate gyrus.…”

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

“…23 The selective PI3-kinase inhibitors wortmannin and LY294002 caused dose- To assess the influence of IGF-1 on MS, SH-SY5Y cells were treated identically to PLM studies and assayed for enzyme activity, measured as the conversion of homocysteine to methionine. As shown in Table 1, IGF-1 increased MS activity to 212% of the basal level.…”