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Sustained activation of M-Ras induced by nerve growth factor is essential for neuronal differentiation of PC12 cells.
Genes Cells. 2006 Sep; 11(9):1097-113.GC

Abstract

Neuronal differentiation in PC12 cells induced by nerve growth factor (NGF) requires sustained activation of ERK/MAP kinase pathway (Raf-MEK-ERK cascade). Although classical Ras (H-Ras, K-Ras, and N-Ras) activated by NGF signaling induces activation of ERK pathway, the activation is transient and not sufficient for PC12 cell differentiation. Instead, it has been widely accepted that NGF signaling-mediated Rap1 activation causes sustained activation of ERK pathway. There has been no direct evidence, however, that Rap1 participates in neuronal differentiation. Here we show that NGF signaling induces sustained activation of M-Ras and subsequent sustained activation of ERK pathway and the transcription factor CREB leading to PC12 cell differentiation. Exogenously expressed constitutively active mutant of M-Ras caused neurite outgrowth in PC12 cells and activating phosphorylation of ERK, whereas activated Rap1 did not. Knockdown of endogenous M-Ras by small interfering RNAs as well as the expression of a dominant-negative mutant of M-Ras interfered with NGF-induced neuritogenesis. Since MEK inhibitors prevented M-Ras-induced neurite outgrowth, ERK pathway participates in this differentiation pathway. Furthermore, M-Ras brought about ERK pathway-mediated activating phosphorylation of CREB and the CREB-mediated transcription. In addition, a dominant-negative mutant of CREB inhibited M-Ras-induced neuritogenesis. Taken together, NGF-induced PC12 cell differentiation requires M-Ras-ERK pathway-mediated activation of CREB. M-Ras was predominantly expressed in the hippocampus and cerebellum of mouse brain and in the gray matter of the spinal cord. All these properties of M-Ras were apparently indistinguishable from those of H-Ras. However, NGF stimulation caused transient activation of classical Ras proteins but sustained activation of M-Ras as well as sustained activating phosphorylation of ERK and CREB. Therefore, M-Ras is essential for neuronal differentiation in PC12 cells by inducing sustained activation of ERK pathway.

Authors+Show Affiliations

Department of Biology, Faculty of Science, and Graduate School of Science and Technology, Chiba University, Yayoicho, Inageku, Chiba, Chiba 263-8522, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16923128

Citation

Sun, Peng, et al. "Sustained Activation of M-Ras Induced By Nerve Growth Factor Is Essential for Neuronal Differentiation of PC12 Cells." Genes to Cells : Devoted to Molecular & Cellular Mechanisms, vol. 11, no. 9, 2006, pp. 1097-113.
Sun P, Watanabe H, Takano K, et al. Sustained activation of M-Ras induced by nerve growth factor is essential for neuronal differentiation of PC12 cells. Genes Cells. 2006;11(9):1097-113.
Sun, P., Watanabe, H., Takano, K., Yokoyama, T., Fujisawa, J., & Endo, T. (2006). Sustained activation of M-Ras induced by nerve growth factor is essential for neuronal differentiation of PC12 cells. Genes to Cells : Devoted to Molecular & Cellular Mechanisms, 11(9), 1097-113.
Sun P, et al. Sustained Activation of M-Ras Induced By Nerve Growth Factor Is Essential for Neuronal Differentiation of PC12 Cells. Genes Cells. 2006;11(9):1097-113. PubMed PMID: 16923128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sustained activation of M-Ras induced by nerve growth factor is essential for neuronal differentiation of PC12 cells. AU - Sun,Peng, AU - Watanabe,Haruko, AU - Takano,Kazunori, AU - Yokoyama,Takashi, AU - Fujisawa,Jun-ichi, AU - Endo,Takeshi, PY - 2006/8/23/pubmed PY - 2006/12/14/medline PY - 2006/8/23/entrez SP - 1097 EP - 113 JF - Genes to cells : devoted to molecular & cellular mechanisms JO - Genes Cells VL - 11 IS - 9 N2 - Neuronal differentiation in PC12 cells induced by nerve growth factor (NGF) requires sustained activation of ERK/MAP kinase pathway (Raf-MEK-ERK cascade). Although classical Ras (H-Ras, K-Ras, and N-Ras) activated by NGF signaling induces activation of ERK pathway, the activation is transient and not sufficient for PC12 cell differentiation. Instead, it has been widely accepted that NGF signaling-mediated Rap1 activation causes sustained activation of ERK pathway. There has been no direct evidence, however, that Rap1 participates in neuronal differentiation. Here we show that NGF signaling induces sustained activation of M-Ras and subsequent sustained activation of ERK pathway and the transcription factor CREB leading to PC12 cell differentiation. Exogenously expressed constitutively active mutant of M-Ras caused neurite outgrowth in PC12 cells and activating phosphorylation of ERK, whereas activated Rap1 did not. Knockdown of endogenous M-Ras by small interfering RNAs as well as the expression of a dominant-negative mutant of M-Ras interfered with NGF-induced neuritogenesis. Since MEK inhibitors prevented M-Ras-induced neurite outgrowth, ERK pathway participates in this differentiation pathway. Furthermore, M-Ras brought about ERK pathway-mediated activating phosphorylation of CREB and the CREB-mediated transcription. In addition, a dominant-negative mutant of CREB inhibited M-Ras-induced neuritogenesis. Taken together, NGF-induced PC12 cell differentiation requires M-Ras-ERK pathway-mediated activation of CREB. M-Ras was predominantly expressed in the hippocampus and cerebellum of mouse brain and in the gray matter of the spinal cord. All these properties of M-Ras were apparently indistinguishable from those of H-Ras. However, NGF stimulation caused transient activation of classical Ras proteins but sustained activation of M-Ras as well as sustained activating phosphorylation of ERK and CREB. Therefore, M-Ras is essential for neuronal differentiation in PC12 cells by inducing sustained activation of ERK pathway. SN - 1356-9597 UR - https://www.unboundmedicine.com/medline/citation/16923128/Sustained_activation_of_M_Ras_induced_by_nerve_growth_factor_is_essential_for_neuronal_differentiation_of_PC12_cells_ L2 - https://doi.org/10.1111/j.1365-2443.2006.01002.x DB - PRIME DP - Unbound Medicine ER -