β-Arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated switching of β2-adrenoceptor signalling to activation of ERK

2005 ◽  
Vol 33 (6) ◽  
pp. 1333-1336 ◽  
Author(s):  
M.D. Houslay ◽  
G.S. Baillie
Keyword(s):  
Functional Role ◽  
Dominant Negative ◽  
Functional Importance ◽  
Extracellular Signal Regulated Kinase ◽  
Phosphodiesterase 4 ◽  
Camp Synthesis ◽  
Extracellular Signal ◽  
Anchoring Protein ◽  
Interfering Rna

Using combined dominant-negative and siRNA (small interfering RNA)-mediated knockdown strategies, the functional importance of specific PDE4 (phosphodiesterase-4) isoforms in modifying signalling through the β2-AR (β2-adrenoceptor) has been uncovered. The PDE4D5 isoform preferentially interacts with the signalling scaffold protein β-arrestin and is thereby recruited to the β2-AR upon agonist challenge. Delivery of an active PDE to the site of cAMP synthesis at the plasma membrane specifically attenuates the activity of a pool of PKA (protein kinase A) that is tethered to the β2-AR via AKAP79 (A-kinase anchoring protein 79). The specific functional role of this anchored PKA is to phosphorylate the β2-AR and allow it to switch its coupling with Gi and thereby activation of ERK (extracellular-signal-regulated kinase). Our studies uncover a novel facet of the regulation of β2-AR signalling by showing that β-arrestin-recruited PDE4 provides the means of desensitizing the agonist-dependent coupling of β2-AR with Gi and its consequential activation of ERK.

MAPK-induced Ser727 phosphorylation promotes SUMOylation of STAT1

2007 ◽  
Vol 409 (1) ◽  
pp. 179-185 ◽  
Author(s):  
Sari Vanhatupa ◽  
Daniela Ungureanu ◽  
Maija Paakkunainen ◽  
Olli Silvennoinen
Keyword(s):  
Interferon Γ ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Microbial Infections ◽  
Mitogen Activated Protein ◽  
P38mapk Pathway ◽  
Ifn Γ

STAT1 (signal transducer and activator of transcription 1) is a critical mediator of IFN-γ (interferon-γ)-induced gene responses, and its function is regulated through phosphorylation of Tyr701 and Ser727. MAPK (mitogen-activated protein kinase) pathways mediate phosphorylation of Ser727 in response to microbial infections, stress stimuli and growth factors. Recently, STAT1 was found to become modified by PIAS (protein inhibitor of activated STAT)-mediated SUMO-1 (small ubiquitin-related modifier-1) conjugation at Lys703, but the regulation of this modification is largely unknown. Here, we have investigated the role of MAPK-induced Ser727 phosphorylation in regulation of STAT1 SUMOylation. Activation of the p38MAPK pathway by upstream activating kinase, MKK6 (MAPK kinase-6) or osmotic stress enhanced the SUMOylation of STAT1, which was counteracted by the p38MAPK inhibitor SB202190 or by dominant-negative p38MAPK. Activation of the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway by Raf-1 also enhanced Ser727 phosphorylation and SUMOylation of STAT1, and this induction was counteracted by PD98059 inhibitor. Mutation of Ser727 to alanine abolished the p38MAPK-induced SUMOylation. Furthermore, S727D and S727E mutations, which mimic the phosphorylation of Ser727, enhanced the basal SUMOylation of STAT1 and interaction between PIAS1 and STAT1. Taken together, these results identify Ser727 phosphorylation as a regulator of STAT1 SUMOylation and highlight the central role of Ser727 in co-ordination of STAT1 functions in cellular responses.

Lipopolysaccharide stimulation of ERK1/2 increases TNF-α production via Egr-1

2002 ◽  
Vol 282 (6) ◽  
pp. C1205-C1211 ◽  
Author(s):  
Liang Shi ◽  
Raj Kishore ◽  
Megan R. McMullen ◽  
Laura E. Nagy
Keyword(s):  
Dominant Negative ◽  
Protein Accumulation ◽  
Extracellular Signal Regulated Kinase ◽  
Early Growth Response ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor ◽  
Dependent Mechanism

Lipopolysaccharide (LPS) is a potent activator of tumor necrosis factor-α (TNF-α) production by macrophages. LPS stimulates the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and increases TNF-α mRNA and protein accumulation in RAW 264.7 murine macrophages. However, the role of ERK1/2 activation in mediating LPS-stimulated TNF-α production is not well understood. Inhibition of ERK1/2 activation with PD-98059 or overexpression of dominant negative ERK1/2 decreased LPS-induced TNF-α mRNA quantity. LPS rapidly increased early growth response factor (Egr)-1 binding to the TNF-α promoter; this response was blunted in cells treated with PD-98059 or transfected with dominant-negative ERK1/2. Using a chloramphenicol acetyltransferase reporter gene linked to the Egr-1 promoter, we show that LPS increased Egr-1 promoter activity via an ERK1/2-dependent mechanism. These results delineate the role of ERK1/2 activation of Egr-1 activity in mediating LPS-induced increases in TNF-α mRNA expression in macrophages.

ERK5 and its role in tumour development

2012 ◽  
Vol 40 (1) ◽  
pp. 251-256 ◽  
Author(s):  
Pamela A. Lochhead ◽  
Rebecca Gilley ◽  
Simon J. Cook
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Invasion And Migration ◽  
Extracellular Signal Regulated Kinase ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Tumour Cell Invasion ◽  
And Migration

The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the ‘hallmarks of cancer’ as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer.

cAMP and Extracellular Signal-Regulated Kinase Signaling in Response to d-Amphetamine and Methylphenidate in the Prefrontal Cortex in Vivo: Role of β1-Adrenoceptors

2005 ◽  
Vol 68 (2) ◽  
pp. 421-429 ◽  
Author(s):  
Vincent Pascoli ◽  
Emmanuel Valjent ◽  
Anne-Gaëlle Corbillé ◽  
Jean-Christophe Corvol ◽  
Jean-Pol Tassin ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Kinase Signaling ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

scholarly journals The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 439 ◽  
Author(s):  
Vanessa Delcroix ◽  
Olivier Mauduit ◽  
Nolwenn Tessier ◽  
Anaïs Montillaud ◽  
Tom Lesluyes ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Therapy Resistance ◽  
High Grade ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Well Differentiated

By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca2+)-response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca2+-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca2+-responses and demonstrated that KL increases the reticular Ca2+-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS.

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