Balance Between S6K-S6 and 4E-BP1 Depends on ERK Activity in Developing Neurons

Ichiro      Nishimura; Kanji      Mori; Yoshitaka      Matsusue; Hidetoshi      Okabe; Tokuhiro      Chano

Abstract

In order to evaluate the role of translational regulator pathways between p70 S6 kinase (S6K), S6 ribosomal protein (S6) and eIF4E binding protein 1 (4E-BP1) in the development of neurons, we analyzed their phosphorylated status in embryo, fetus and adult murine tissues, and compared neurons with the other types of cells. Phosphorylated 4EBP1 was abundantly present in all kinds of tissues during the entire course of development. S6K and S6 activities were highly maintained in the neurons from embryo to adult, while they were decreasing in the other types of cells from prenatal 17-19dpc fetus to mature adults. Assessing the differentiation in Neuro-2a neuronal and C2C12 muscle cells, we found that extracellular signal-regulated kinase (ERK) activity contributed to the conserved activities of S6K-S6, neurite growth and differentiation in the developing neurons. The translational balance between S6K-S6 and 4E-BP1 plays important roles in the developing embryo and fetus, and the highly preserved S6K-S6 activities are required for adequate development of neuronal cells and probably for glucose homeostasis in the neuron. Impaired ERK activity causes disturbances in the neurite growth and the differentiation of developing neurons, and may deregulate the control of whether neurons die or stay alive.

Keywords: S6 ribosomal protein (S6), eIF4E binding protein 1 (4E-BP1), extracellular signal-regulated kinase (ERK), neuron, embryo, p70 S6 kinase, eIF4E, rapamycin complex 1 (mTORC1), ERK, 3,3'-diaminobenzidine tetrahydrochloride (DAB), Western Blotting, SDS-PAGE, PVDF, Neurite Formation Assay