scholarly journals Signal transduction by nerve growth factor and fibroblast growth factor in PC12 cells requires a sequence of src and ras actions.

1991 ◽  
Vol 115 (3) ◽  
pp. 809-819 ◽  
Author(s):  
N E Kremer ◽  
G D'Arcangelo ◽  
S M Thomas ◽  
M DeMarco ◽  
J S Brugge ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Pc12 Cells ◽  
Neurite Growth ◽  
Signal Transduction Pathways ◽  
Fibroblast Growth ◽  
Ras Oncogene ◽  
Ras Proteins

We have investigated the roles of pp60c-src and p21c-ras proteins in transducing the nerve growth factor (NGF) and fibroblast growth factor (FGF) signals which promote the sympathetic neuronlike phenotype in PC12 cells. Neutralizing antibodies directed against either Src or Ras proteins were microinjected into fused PC12 cells. Each antibody both prevented and reversed NGF- or FGF-induced neurite growth, a prominent morphological marker for the neuronal phenotype. These data demonstrate the involvement of both pp60c-src and p21c-ras proteins in NGF and FGF actions in PC12 cells, and establish a physiological role for the pp60c-src tyrosine kinase in signal transduction pathways initiated by receptor tyrosine kinases in these cells. Additional microinjection experiments, using PC12 transfectants containing inducible v-src or ras oncogene activities, demonstrated a specific sequence of Src and Ras actions. Microinjection of anti-Ras antibody blocked v-src-induced neurite growth, but microinjection of anti-Src antibodies had no effect on ras oncogene-induced neurite growth. We propose that a cascade of Src and Ras actions, with Src acting first, is a significant feature of the signal transduction pathways for NGF and FGF. The Src-Ras cascade may define a functional cassette in the signal transduction pathways used by growth factors and other ligands whose receptors have diverse structures and whose range of actions on various cell types include mitogenesis and differentiation.

scholarly journals Cross talk among tyrosine kinase receptors in PC12 cells: desensitization of mitogenic epidermal growth factor receptors by the neurotrophic factors, nerve growth factor and basic fibroblast growth factor.

1993 ◽  
Vol 4 (7) ◽  
pp. 737-746 ◽  
Author(s):  
I Mothe ◽  
R Ballotti ◽  
S Tartare ◽  
A Kowalski-Chauvel ◽  
E Van Obberghen
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Fibroblast Growth Factor ◽  
Pc12 Cells ◽  
Binding Sites ◽  
Egf Receptor ◽  
Fibroblast Growth ◽  
High Affinity ◽  
Epidermal Growth

We have studied the effects of nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) on epidermal growth factor (EGF) binding to PC12 cells. We show that NGF and bFGF rapidly induce a reduction in 125I-EGF binding to PC12 cells in a dose-dependent manner. This decrease amounts to 50% for NGF and 35% for bFGF. Both factors appear to act through a protein kinase C(PKC)-independent pathway, because their effect persists in PKC-downregulated PC12 cells. Scatchard analysis indicates that NGF and bFGF decrease the number of high affinity EGF binding sites. In addition to their effect on EGF binding, NGF and bFGF activate in intact PC12 cells one or several serine/threonine kinases leading to EGF receptor threonine phosphorylation. Using an in vitro phosphorylation system, we show that NGF- or bFGF-activated extracellular regulated kinase 1 (ERK1) is able to phosphorylate a kinase-deficient EGF receptor. Phosphoamino acid analysis indicates that this phosphorylation occurs mainly on threonine residues. Furthermore, two comparable phosphopeptides are observed in the EGF receptor, phosphorylated either in vivo after NGF treatment or in a cell-free system by NGF-activated ERK1. Finally, a good correlation was found between the time courses of ERK1 activation and 125I-EGF binding inhibition after NGF or bFGF treatment. In conclusion, in PC12 cells the NGF- and bFGF-stimulated ERK1 appears to be involved in the induction of the threonine phosphorylation of the EGF receptor and the decrease in the number of high affinity EGF binding sites.

scholarly journals Effect of nerve growth factor and fibroblast growth factor on PC12 cells: inhibition by orthovanadate.

1993 ◽  
Vol 121 (2) ◽  
pp. 409-422 ◽  
Author(s):  
Y Y Wu ◽  
R A Bradshaw
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Pc12 Cells ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Phosphatases ◽  
Secondary Response ◽  
Fibroblast Growth ◽  
Tyrosine Phosphatases ◽  
Nerve Growth

Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, causes increased levels of tyrosine phosphorylation and blocks, at noncytotoxic concentrations, the differentiative response of rat pheochromocytoma (PC12) cells to beta-nerve growth factor (beta NGF) and basic fibroblast growth factor (bFGF) in a reversible manner. It also prevents growth factor-induced neurite proliferation in primed cells and causes the retraction of previously formed neurites, even in the presence of beta NGF or bFGF. It is equally effective in blocking neurite proliferation by 8-Br-cAMP. Zinc chloride and ammonium molybdate, two other inhibitors of tyrosine phosphatases, also cause parallel decreases in neurite proliferation. Orthovanadate generally reduces the transcription of immediate early response genes (TIS 8 and c-fos) and secondary response genes (ornithine decarboxylase (ODC), acetyl-cholinesterase (AChE) and SCG 10) induced by beta NGF, bFGF, EGF, and PMA, albeit in a variable fashion. There was no observed effect on the kinetics of expression as judged by TIS 8 induction by beta NGF and protein kinase C (PKC) downregulation did not change the levels of inhibition by orthovanadate seen in control cells. Orthovanadate does not affect the production of diacylglycerol induced by beta NGF or bFGF. These observations are consistent with the view that growth factor stimulation of differentiation in PC12 cells involves at least one other PKC independent pathway, and that cAMP and PMA (and their active analogs) activate tyrosine kinases (albeit probably secondarily), which are at least partially responsible for their actions. Although the exact site(s) of action of orthovanadate that lead to the inhibition of growth factor-induced neurite proliferation are unknown, the results presented suggest that it prolongs tyrosine phosphorylations by nonreceptor tyrosine kinases that act downstream from the receptor kinases.

scholarly journals Divergence in the anti-apoptotic signalling pathways used by nerve growth factor and basic fibroblast growth factor (bFGF) in PC12 cells: rescue by bFGF involves protein kinase Cδ

2000 ◽  
Vol 352 (1) ◽  
pp. 175-182 ◽  
Author(s):  
Maribeth M. WERT ◽  
H. Clive PALFREY
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Map Kinase ◽  
Fibroblast Growth Factor ◽  
Pc12 Cells ◽  
Basic Fibroblast Growth Factor ◽  
Dominant Negative ◽  
Signalling Pathways ◽  
Fibroblast Growth

The mechanisms whereby nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) block apoptosis in serum-deprived PC12 cells were investigated. NGF, but not bFGF, strongly activated Akt/protein kinase B, a downstream effector of phosphoinositide (phosphatidylinositol) 3-kinase (PI 3-kinase). In addition, inhibition of PI 3-kinase by LY294002 partially blocked inhibition of apoptosis by NGF, but not that by bFGF, suggesting divergence in NGF and bFGF anti-apoptotic signalling pathways. Both growth factors strongly activated mitogen-activated protein (MAP) kinases, but blockade of signalling through this pathway, either by the expression of dominant-negative Ras or by treatment with the MAP kinase/ERK kinase (MEK) inhibitor U0126, partially inhibited only bFGF, but not NGF, anti-apoptotic signalling. Use of isoform-specific protein kinase C (PKC) inhibitors such as bisindoylmaleimide-I and Gö 6983 suggested that PKCδ is a likely component of bFGF trophic signalling. A role for PKCδ was confirmed in PC12 cells expressing a dominant-negative PKCδ fragment, in which reversal of apoptosis by bFGF was partially blocked. The PKCδ signal was not mediated by the MAP kinase cascade, as bFGF activation of this pathway was not affected in cells expressing the dominant-negative PKCδ fragment. Full inhibition of bFGF anti-apoptotic signalling occurred when both the PKCδ and Ras/MAP kinase pathways were inhibited. Together, these data demonstrate that inhibition of apoptosis by bFGF in PC12 cells operates differently from that mediated by NGF, requiring the addition of signals from both the Ras/MAP kinase and PKC signalling pathways.

scholarly journals Growth Inhibitory Effect of Fibroblast Growth Factor Peptide Antagonist on Mouse Model Breast Tumor through ERK/MAPK and PI3K/AKT Signaling Pathways

2019 ◽  
Author(s):  
mehrzad jafarzadeh ◽  
Kazem Mousavizadeh ◽  
Mohammad hashemi Bahremani ◽  
S.mohsen Asghari
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Fibroblast Growth Factor ◽  
Metastatic Breast ◽  
Negative Control ◽  
Signal Transduction Pathways ◽  
Control Group ◽  
Fibroblast Growth ◽  
Erk Mapk

Abstract Background In the majority of cancers, metastasis of tumor cells is main cause of treatment failure. The current research investigated the effectiveness basic fibroblast growth factor (bFGF) peptide developed to inhibit tumor growth in 4T1 metastatic breast cancer through the PI3K/AKT and ERK/MAPK signal transduction pathways. In BALB/c mice, the tumor was induced through 4T1 tumor graft. Administration of the peptide was done one time a day at various doses of 1, 2.5, or 10 mg/kg over 14 days. After two weeks, the designed peptide injected .After the treatment period, the mice underwent surgery, and tumors were used for the Immunohistochemistry, Apoptosis, and western blot examinations.Results Based on one-way ANOVA and p ≤0.05, findings showed that the P-AKT and p-ERK contents in tumors treated with peptide reduced in two mentioned signaling pathways and the peptide injection were effective in reducing or inhibiting tumor growth.Conclusion Our findings showed that in the two signal transduction pathways, the P-AKT and p-ERK levels were significantly different from the negative control group.

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