Two Different Signal Transduction Pathways Are Implicated in the Regulation of Initiation Factor 2B Activity in Insulin-like Growth Factor-1-stimulated Neuronal Cells

Abstract

Eukaryotic initiation factor eIF-2B plays an important role in translation regulation and has been suggested to be implicated in the increased protein synthesis promoted in response to growth factors. We have used primary cultured neurons to delineate the signaling pathways by which insulin-like growth factor-1 (IGF-1), which plays a critical role in the survival of neuronal cells, promotes eIF-2B and protein synthesis activation. Treatment of cortical neurons with IGF-1 (100 ng/ml) for 30 min stimulates [ 3 H]methionine incorporation, and a parallel increase in eIF-2B activity was observed. Wortmannin and LY294002 reversed both effects, indicating that phosphatidylinositol 3-kinase mediates IGF-1-induced protein synthesis and eIF-2B activation. IGF-1 induced glycogen synthase kinase-3 (GSK-3) inactivation in a phosphatidylinositol 3-kinasedependent fashion because it is inhibited by wortmannin and LY294002. By using GSK-3 immunoprecipitated from untreated and IGF-1-treated cells, we demonstrate the phosphorylation of eIF-2B coincident with its inactivation. The treatment of cortical neurons with IGF-1 also promoted the activation of mitogen-activated protein kinase (MAPK). The MAPK-activating kinase (MEK) inhibitor PD98059 inhibited MAPK activation and reversed IGF-1-induced protein synthesis and eIF-2B activation. These findings suggest that IGF-1-induced eIF-2B activation on neurons is promoted through phosphatidylinositol 3-kinase and GSK-3 kinase, and we report an IGF-1-induced MEK/MAPK activation pathway implicated in eIF-2B activation.

Water Extract of Korean Red Ginseng Stimulates Angiogenesis by Activating the PI3K/Akt-Dependent ERK1/2 and eNOS Pathways in Human Umbilical Vein Endothelial Cells

“…19) In some systems, these processes were found to be independently activated and equally important for angiogenic activity, 29) whereas in others, PI3K or ERK signaling played more dominant roles. 30) Our data showed that KRGE activated the MEK/ERK1/2, PI3K/Akt, and eNOS/NOS pathways, which were critically involved in its angiogenic activity.…”

Dual Regulation of MMP-2 Expression by the Type 1 Insulin-like Growth Factor Receptor

“…PI 3-kinase has been identified as the major transducer of the IGF-IR signal in other cellular systems, and its activity was shown to be critical for IGF-I-induced cell survival, mitogenesis, and transcriptional and translational regulation of protein synthesis (16,(47)(48)(49)(50)(51)(52). In some systems, these processes were found to be equally dependent on ERK signaling (47,50), whereas in others, the PI 3-kinase pathway or ERK signaling played more dominant roles (48,53).…”

“…In some systems, these processes were found to be equally dependent on ERK signaling (47,50), whereas in others, the PI 3-kinase pathway or ERK signaling played more dominant roles (48,53). The degree to which different cells utilize these pathways to convey IGF-IR signals may be cell context-dependent and could be determined, among others, by the levels and accessibility of downstream substrates such as insulin receptor substrate-1 or Shc (40,53,54) and by the repertoires and activation levels of other receptor tyrosine kinasess, such as the epidermal growth factor receptor, expressed by the cells (56).…”

Insulin-like growth factor I and Alzheimer´s disease: therapeutic prospects?

“…At the cellular level IGF-I can increase neuronal survival and protect neurons against the toxicity of amyloid peptides [15][16][17]. Through activation of the phosphatidylinositol 3 kinase (PI3K)/Akt pathway IGF-I also inhibits glycogen synthetase kinase (GSK)-3β, a Tau-kinase thought to be involved in hyperphosphorylation of tau, the major component of neurofibrillary tangles [18,19]. In addition, through its ability to modulate insulin sensitivity, IGF-I, which may also participate in the loss of neuronal sensitivity to insulin recently reported in Alzheimer's patients [8,20,21].…”