Activation of mitogen-activated protein kinases is not required for the extension of neurites from PC12D Cells triggered by nerve growth factor

Sano, Mamoru; Kitajima, Satoko

doi:10.1016/s0006-8993(97)01403-0

Cited by 37 publications

(24 citation statements)

References 43 publications

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“…This phenotype is mediated in part by Ras-induced Raf activation, since constitutively activated versions of Raf can mimic, at least to some extent, the effects of activated Ras (53). Moreover, inhibition of the Ras-Raf-Erk pathway blocks stimulus-induced neurite outgrowth (40). Similar conclusions have been reached for Ras-induced PI3 kinase activity (16,25).…”

Section: Discussionsupporting

confidence: 54%

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Ral-Specific Guanine Nucleotide Exchange Factor Activity Opposes Other Ras Effectors in PC12 Cells by Inhibiting Neurite Outgrowth

Goi

Rusanescu

Urano

et al. 1999

Molecular and Cellular Biology

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Ras proteins can activate at least three classes of downstream target proteins: Raf kinases, phosphatidylinositol-3 phosphate (PI3) kinase, and Ral-specific guanine nucleotide exchange factors (Ral-GEFs). In NIH 3T3 cells, activated Ral-GEFs contribute to Ras-induced cell proliferation and oncogenic transformation by complementing the activities of Raf and PI3 kinases. In PC12 cells, activated Raf and PI3 kinases mediate Ras-induced cell cycle arrest and differentiation into a neuronal phenotype. Here, we show that in PC12 cells, Ral-GEF activity acts opposite to other Ras effectors. Elevation of Ral-GEF activity induced by transfection of a mutant Ras protein that preferentially activates Ral-GEFs, or by transfection of the catalytic domain of the Ral-GEF Rgr, suppressed cell cycle arrest and neurite outgrowth induced by nerve growth factor (NGF) treatment. In addition, Rgr reduced neurite outgrowth induced by a mutant Ras protein that preferentially activates Raf kinases. Furthermore, inhibition of Ral-GEF activity by expression of a dominant negative Ral mutant accelerated cell cycle arrest and enhanced neurite outgrowth in response to NGF treatment. Ral-GEF activity may function, at least in part, through inhibition of the Rho family GTPases, CDC42 and Rac. In contrast to Ras, which was activated for hours by NGF treatment, Ral was activated for only ϳ20 min. These findings suggest that one function of Ral-GEF signaling induced by NGF is to delay the onset of cell cycle arrest and neurite outgrowth induced by other Ras effectors. They also demonstrate that Ras has the potential to promote both antidifferentiation and prodifferentiation signaling pathways through activation of distinct effector proteins. Thus, in some cell types the ratio of activities among Ras effectors and their temporal regulation may be important determinants for cell fate decisions between proliferation and differentiation.

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Section: Discussionsupporting

confidence: 54%

“…First, activated forms of Raf or PI3 kinases can produce, at least in part, effects similar to those of activated Ras (25,53). Second, inhibition of the Ras-Raf-Erk kinase cascade (40) or PI3 kinase activity (16) prevents NGF-induced neurite outgrowth. The kinetics and magnitude of signaling pathway stimulation may also be important.…”

mentioning

confidence: 99%

Ral-Specific Guanine Nucleotide Exchange Factor Activity Opposes Other Ras Effectors in PC12 Cells by Inhibiting Neurite Outgrowth

Goi

Rusanescu

Urano

et al. 1999

Molecular and Cellular Biology

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“…S2C). Dissociation of neurite outgrowth from these events had already been reported in another PC12 clone, PC12D (Sano et al, 1998). In that clone, however, the nature of the exocytic organelles sustaining neurite outgrowth had not been investigated.…”

Section: Rapid Neurite Outgrowth In Pc12-27 and Sh-sy5y Cellsmentioning

confidence: 92%

Rapid neurite outgrowth in neurosecretory cells and neurons is sustained by the exocytosis of a cytoplasmic organelle, the enlargeosome

Racchetti

Lorusso

Schulte

et al. 2010

Journal of Cell Science

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SummaryNeurite outgrowth is known as a slow (days) process occurring in nerve cells and neurons during neurotrophin treatment and upon transfer to culture, respectively. Using Y27632, a drug that induces activation of Rac1, a downstream step of the neurotrophin signaling cascade, we have identified a new form of outgrowth, which is rapid (<1 hour) and extensive (>500 mm 2 surface enlargement/single cell/first hour). However, this outgrowth takes place only in cells (PC12-27 and SH-SY5Y cells, and embryonic and neonatal neurons) rich in an exocytic organelle, the enlargeosome. Golgi vesicles, TGN vesicles and endosomes are not involved. The need for enlargeosomes for plasma-membrane expansion was confirmed by the appearance of their marker, Ahnak, at the cell surface and by the dependence of neurite outgrowth on VAMP4, the vSNARE of enlargeosome exocytosis. In enlargeosome-rich cells, VAMP4 downregulation also attenuated the slow outgrowth induced by nerve growth factor (NGF). Similar to NGF-induced neurite outgrowth in enlargeosomelacking cells, the new, rapid, Y27632-induced process required microtubules. Other properties of neurite outgrowth in cells lacking enlargeosomes -such as dependence on VAMP7, on microfilaments, on gene transcription and on protein synthesis, and blockade of mitoses and accumulation of neuronal markers -were not evident. The enlargeosome-sustained process might be useful for the rapid neurite outgrowth at peculiar stages and/or conditions of nerve and neuronal cells. However, its properties and its physiological and pathological role remain to be investigated.

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“…ERK/MAP kinases are activated through phosphorylation by MEK, a mechanism blocked by PD98059. This MEK blocker was also shown to abolish internalization of MOR and DOR (Kramer et al, 2000;Schmidt et al, 2000) by using concentrations of the compound that are considered to bring about cytotoxic effects (Sano and Kitajima, 1998). We report here that PD98059 (10 M) fails to affect cell viability and enables morphine to strongly induce DOR internalization.…”

Section: Discussionmentioning

confidence: 61%

Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinases Block Internalization of δ-Opioid Receptors

Eisinger¹,

Schulz²

2004

J Pharmacol Exp Ther

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Translocation of G protein-coupled receptors (GPCRs) from the cell membrane to cytosol depends on the kind of ligand activating the receptor. This principle is clearly demonstrated for opioid receptors, because diverse opiate agonists rapidly induce receptor internalization, whereas morphine almost fails. We report here the impact of mitogen-activated protein (MAP) kinase isoforms extracellular signal-regulated kinase (ERK)1/2 on the internalization of ␦-opioid receptors (DORs) expressed in human embryonic kidney (HEK)293 cells. Receptor activation by etorphine turned out to transiently phosphorylate ERK/MAP kinases and bring about DOR internalization within 20 min. In contrast, prolonged exposure of HEK293 cells to morphine excited persistent phosphorylation of ERK/MAP kinases, and those cells failed to internalize the opioid receptor. When ERK/ MAP kinase phosphorylation was blocked by 2Ј-Amino-3Ј-methoxyflavone (PD98059), morphine gained the ability to strongly induce DOR endocytosis. The importance of activated MAP kinases for DOR internalization is further demonstrated by glutamate and paclitaxel because these substances induce phosphorylation of ERK1/2 and concomitantly prevent DOR sequestration by etorphine. In addition, receptor internalization by morphine was facilitated by inhibition of protein kinase C and opioid-mediated transactivation of epidermal growth factor receptor (EGFR), both activating ERK/MAP kinases by opioids. The mechanism affording DOR internalization by PD98059 may relate to arrestin, which uncouples GPCRs and thus triggers receptor internalization. Arrestin considerably translocates toward the cell membrane upon DOR activation by morphine in presence of the MAP kinase blocker, but it fails in the absence of PD98059. We conclude that ERK/MAP kinase activity prevents opioid receptor desensitization and sequestration by blocking arrestin 2 interaction with activated DORs.

show abstract

Activation of mitogen-activated protein kinases is not required for the extension of neurites from PC12D Cells triggered by nerve growth factor

Cited by 37 publications

References 43 publications

Ral-Specific Guanine Nucleotide Exchange Factor Activity Opposes Other Ras Effectors in PC12 Cells by Inhibiting Neurite Outgrowth

Ral-Specific Guanine Nucleotide Exchange Factor Activity Opposes Other Ras Effectors in PC12 Cells by Inhibiting Neurite Outgrowth

Rapid neurite outgrowth in neurosecretory cells and neurons is sustained by the exocytosis of a cytoplasmic organelle, the enlargeosome

Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinases Block Internalization of δ-Opioid Receptors

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