Agonist-Dependent Modulation of G Protein-Coupled Receptor Kinase 2 by Mitogen-Activated Protein Kinases

2000 ◽  
Vol 57 (4) ◽  
pp. 778-783 ◽  
Author(s):  
Ana Elorza ◽  
Susana Sarnago ◽  
Federico Mayor
Keyword(s):  
Protein Kinases ◽  
G Protein ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein ◽  
G Protein Coupled

scholarly journals A Network of Mitogen-Activated Protein Kinases Links G Protein-Coupled Receptors to the c-jun Promoter: a Role for c-Jun NH2-Terminal Kinase, p38s, and Extracellular Signal-Regulated Kinase 5

1999 ◽  
Vol 19 (6) ◽  
pp. 4289-4301 ◽  
Author(s):  
Maria Julia Marinissen ◽  
Mario Chiariello ◽  
Michael Pallante ◽  
J. Silvio Gutkind
Keyword(s):  
Signaling Pathway ◽  
Protein Kinases ◽  
G Protein ◽  
Intracellular Signaling ◽  
Temporal Integration ◽  
Regulatory Elements ◽  
G Protein Coupled Receptors ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein ◽  
G Protein Coupled

ABSTRACT The expression of the c-jun proto-oncogene is rapidly induced in response to mitogens acting on a large variety of cell surface receptors. The resulting functional activity of c-Jun proteins appears to be critical for cell proliferation. Recently, we have shown that a large family of G protein-coupled receptors (GPCRs), represented by the m1 muscarinic receptor, can initiate intracellular signaling cascades that result in the activation of mitogen-activated protein kinases (MAPK) and c-Jun NH2-terminal kinases (JNK) and that the activation of JNK but not of MAPK correlated with a remarkable increase in the expression of c-jun mRNA. Subsequently, however, we obtained evidence that GPCRs can potently stimulate the activity of the c-jun promoter through MEF2 transcription factors, which do not act downstream from JNK. In view of these observations, we set out to investigate further the nature of the signaling pathway linking GPCRs to the c-jun promoter. Utilizing NIH 3T3 cells, we found that GPCRs can activate the c-jun promoter in a JNK-independent manner. Additionally, we demonstrated that these GPCRs can elevate the activity of novel members of the MAPK family, including ERK5, p38α, p38γ, and p38δ, and that the activation of certain kinases acting downstream from MEK5 (ERK5) and MKK6 (p38α and p38γ) is necessary to fully activate the c-jun promoter. Moreover, in addition to JNK, ERK5, p38α, and p38γ were found to stimulate the c-jun promoter by acting on distinct responsive elements. Taken together, these results suggest that the pathway linking GPCRs to the c-junpromoter involves the integration of numerous signals transduced by a highly complex network of MAPK, rather than resulting from the stimulation of a single linear protein kinase cascade. Furthermore, our findings suggest that each signaling pathway affects one or more regulatory elements on the c-jun promoter and that the transcriptional response most likely results from the temporal integration of each of these biochemical routes.

scholarly journals Role of c-Src Tyrosine Kinase in G Protein-coupled Receptorand Gβγ Subunit-mediated Activation of Mitogen-activated Protein Kinases

1996 ◽  
Vol 271 (32) ◽  
pp. 19443-19450 ◽  
Author(s):  
Louis M. Luttrell ◽  
Brian E. Hawes ◽  
Tim van Biesen ◽  
Deirdre K. Luttrell ◽  
Timothy J. Lansing ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Protein Kinases ◽  
G Protein ◽  
Src Tyrosine Kinase ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein ◽  
G Protein Coupled

scholarly journals Transactivación de receptores con actividad de cinasa de tirosina (RTK’s) por receptores acoplados a proteínas G

2004 ◽  
Vol 15 (1) ◽  
pp. 33-48 ◽  
Author(s):  
Enrique Sánchez-Lemus ◽  
José A Arias-Montaño
Keyword(s):  
Protein Kinases ◽  
G Protein ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
G Protein Coupled Receptors ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein ◽  
G Protein Coupled

Los efectos de los factores de crecimiento y de ciertas hormonas se deben a la activación de receptores con actividad intrínseca de cinasa de tirosina (o RTK’s, por receptor tyrosine kinases), cuya estimulación inicia cascadas de señalización intracelular que regulan eventos transcripcionales esenciales para la proliferación y la diferenciación celulares. Entre los efectos debidos a la estimulación de los RTK’s, destaca la activación de la familia de cinasas de proteína activadas por mitógeno o MAPK’s (mitogen-activated protein kinases). Existen evidencias que indican que la estimulación de algunos receptores acoplados a proteínas G (o GPCR’s, por G protein-coupled receptors) resulta en la activación de RTK’s en ausencia de un ligando para estos últimos. Este proceso ha sido denominado transactivación, y depende de señales intracelulares inducidas por la estimulación de GPCR’s en las que participan tanto las subunidades a como los complejos bg de las proteínas G, así como fenómenos de fosforilación mediados por diferentes cinasas. En este artículo se revisan las características estructurales de ambos tipos de receptores (GPCR’s y RTK’s), los mecanismos responsables de su activación y los procesos involucrados en el fenómeno de transactivación de RTK’s por activación de GPCR’s.

scholarly journals G Protein-coupled Receptor Kinase 2 Negatively Regulates Chemokine Signaling at a Level Downstream from G Protein Subunits

2006 ◽  
Vol 17 (1) ◽  
pp. 25-31 ◽  
Author(s):  
M. Carmen Jiménez-Sainz ◽  
Cristina Murga ◽  
Annemieke Kavelaars ◽  
María Jurado-Pueyo ◽  
Beate F. Krakstad ◽  
...  
Keyword(s):  
G Protein ◽  
Mitogen Activated Protein Kinase ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Hek 293 ◽  
Erk Activation ◽  
Chemokine Signaling ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
G Protein Coupled

The G protein-coupled receptor kinase 2 (GRK2) phosphorylates and desensitizes ligand-activated G protein-coupled-receptors. Here, evidence is shown for a novel role of GRK2 in regulating chemokine-mediated signals. The presence of increased levels of GRK2 in human embryonic kidney (HEK) 293 cells produced a significant reduction of the extracellular signal-regulated kinase (ERK) response to CCL2. This effect is independent of its role in receptor phosphorylation because the kinase-deficient mutant GRK2K220R was able to reduce this response, and ERK activation by CCR2BIX, a phosphorylation-defective receptor mutant, was also inhibited by GRK2. Constructs containing the Gαq-binding RGS-like RH domain of GRK2 or its Gβγ-binding domain could not reproduce the inhibition, thus revealing that GRK2 acts downstream of G proteins. Interestingly, chemokine-driven mitogen-activated protein kinase kinase (MEK) stimulation is not affected in cells overexpressing GRK2 or GRK2K220R or in splenocytes from heterozygous GRK2 mice, where reduced kinase levels correlate with enhanced ERK activation by chemokines. We find GRK2 and MEK in the same multimolecular complex, thus suggesting a mechanism for GRK2 regulation of ERK activity that involves a direct or coordinate interaction with MEK. These results suggest an important role for GRK2 in the control of chemokine induction of ERK activation at the level of the MEK–ERK interface.

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