scholarly journals Nerve Growth Factor Activates Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways To Stimulate CREB Serine 133 Phosphorylation

1998 ◽  
Vol 18 (4) ◽  
pp. 1946-1955 ◽  
Author(s):  
Jun Xing ◽  
Jon M. Kornhauser ◽  
Zhengui Xia ◽  
Elizabeth A. Thiele ◽  
Michael E. Greenberg
Keyword(s):  
Transcription Factor ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Nerve Growth ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Ribosomal S6 Kinase

ABSTRACT The mechanisms by which growth factor-induced signals are propagated to the nucleus, leading to the activation of the transcription factor CREB, have been characterized. Nerve growth factor (NGF) was found to activate multiple signaling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133 (Ser-133). NGF activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs), which in turn activate the pp90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases, all three members of which were found to catalyze CREB Ser-133 phosphorylation in vitro and in vivo. In addition to the ERK/RSK pathway, we found that NGF activated the p38 MAPK and its downstream effector, MAPK-activated protein kinase 2 (MAPKAP kinase 2), resulting in phosphorylation of CREB at Ser-133. Inhibition of either the ERK/RSK or the p38/MAPKAP kinase 2 pathway only partially blocked NGF-induced CREB Ser-133 phosphorylation, suggesting that either pathway alone is sufficient for coupling the NGF signal to CREB activation. However, inhibition of both the ERK/RSK and the p38/MAPKAP kinase 2 pathways completely abolished NGF-induced CREB Ser-133 phosphorylation. These findings indicate that NGF activates two distinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes.

Involvement of Ras/MAP Kinase in the Regulation of Ca2+ Channels in Adult Bullfrog Sympathetic Neurons by Nerve Growth Factor

1998 ◽  
Vol 80 (3) ◽  
pp. 1352-1361 ◽  
Author(s):  
Saobo Lei ◽  
William F. Dryden ◽  
Peter A. Smith
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Map Kinase ◽  
Kinase Inhibitors ◽  
Sympathetic Neurons ◽  
Mitogen Activated Protein Kinase ◽  
Nerve Growth ◽  
Channel Current ◽  
Mitogen Activated Protein

Lei, Saobo, William F. Dryden, and Peter A. Smith. Involvement of Ras/MAP kinase in the regulation of Ca2+ channels in adult bullfrog sympathetic neurons by nerve growth factor. J. Neurophysiol. 80: 1352–1361, 1998. The cellular mechanisms that underlie nerve growth factor (NGF) induced increase in Ca2+-channel current in adult bullfrog sympathetic B-neurons were examined by whole cell recording techniques. Cells were maintained at low density in neuron-enriched, defined-medium, serum-free tissue culture for 6 days in the presence or absence of NGF (200 ng/ml). The increase in Ba2+ current ( I Ba) density induced by NGF was attenuated by the RNA synthesis inhibitor cordycepin (20 μM), by the DNA transcription inhibitor actinomycin D (0.01 μg/ml), by inhibitors of Ras isoprenylation (perillic acid 0.1–1.0 mM or α-hydroxyfarnesylphosphonic acid 10–100 μM), by tyrosine kinase inhibitors genistein (20 μM) or lavendustin A (1 μM), and by PD98059 (10–100 μM), an inhibitor of mitogen-activated protein kinase kinase. Inhibitors of the phosphatidylinositol 3-kinase (PI3K) pathway (wortmannin, 100 nM, or LY29400, 100 μM) were ineffective as were inhibitors of phospholipase Cγ (U73122 or neomycin, both 100 μM). The effect of NGF persisted in Ca2+-free medium that contained 1.8 mM Mg2+ and 2 mM ethylene glycol-bis(β-aminoethyl ether)- N, N, N′, N′-tetraacetic acid. It was mimicked by a Trk antibody that was capable of inducing neurite outgrowth in explant cultures of bullfrog sympathetic ganglion. Antibodies raised against the low-affinity p75 neurotrophin receptor were ineffective in blocking the effect of NGF on I Ba. These results suggest that NGF-induced increase in Ca2+ channel current in adult sympathetic neurons results, at least in part, from new channel synthesis after Trk activation of Ras and mitogen activated protein kinase by a mechanism that is independent of extracellular Ca2+.

Functional components of basic fibroblast growth factor signaling that inhibit lung elastin gene expression

2001 ◽  
Vol 281 (4) ◽  
pp. L766-L775 ◽  
Author(s):  
Isabel Carreras ◽  
Celeste B. Rich ◽  
Julie A. Jaworski ◽  
Sandra J. Dicamillo ◽  
Mikhail P. Panchenko ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Fibroblast Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Activator Protein 1 ◽  
Fibroblast Growth ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Elastin Gene

Previously, we have demonstrated that basic fibroblast growth factor (bFGF) decreases elastin gene transcription in confluent rat lung fibroblasts via the binding of a Fra-1-c-Jun heterodimer to an activator protein-1-cAMP response element in the distal region of the elastin promoter. In the present study, we show that bFGF activates the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2, resulting in the translocation of phosphorylated extracellular signal-regulated kinase 1/2 into the nucleus followed by increased binding of Elk-1 to the serum response element of the c-Fos promoter, transient induction of c-Fos mRNA, and sustained induction of Fra-1 mRNA. The addition of PD-98059, an inhibitor of mitogen-activated protein kinase kinase, abrogates the bFGF-dependent repression of elastin mRNA expression. Comparative analyses of confluent and subconfluent fibroblast cultures reveal significant differences in elastin mRNA levels and activator protein-1 protein factors involved in the regulation of elastin transcription. These findings suggest that bFGF modulates specific cellular events that are dependent on the state of the cell and provide a rationale for the differential responses that can be expected in development and injury or repair situations.

Nerve growth factor functions as a chemoattractant for mast cells through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2052-2058 ◽  
Author(s):  
Junko Sawada ◽  
Atsuko Itakura ◽  
Akane Tanaka ◽  
Tohru Furusaka ◽  
Hiroshi Matsuda
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Mast Cells ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Mitogen Activated Protein Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Directional Migration ◽  
Nerve Growth ◽  
Mitogen Activated Protein

Abstract Despite being a well-characterized neurotrophic factor, nerve growth factor (NGF) influences survival, differentiation, and functions of mast cells. We investigated whether NGF was able to induce directional migration of rat peritoneal mast cells (PMCs). NGF clearly induced chemotactic movement of PMCs in a dose-dependent manner with the drastic morphological change and distribution of F-actin, which was completely blocked by pretreatment with Clostridium botulinumC2 toxin, an actin-polymerization inhibitor. Because PMCs constitutively express the NGF high-affinity receptor (TrkA) with a tyrosine kinase domain, we focused on downstream effectors in signaling cascades following the TrkA. NGF rapidly activated both mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), and the addition of inhibitors specific for MAPK kinase and PI3K suppressed cell migration and these signals. In the coculture system with PMCs and fibroblasts, which produce biologically active NGF, directional migration of PMCs to fibroblasts was observed, and the addition of anti-NGF polyclonal antibodies significantly suppressed the migration of PMCs. These findings suggested that NGF initiated chemotactic movement of PMCs through both MAPK and PI3K signaling pathways following TrkA activation. Thus, locally produced NGF may play an important role in mast cell accumulation in allergic and nonallergic inflammatory conditions.

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