Back to Search
Start Over
Activation of JNK by Epac is independent of its activity as a Rap guanine nucleotide exchanger
- Source :
- The Journal of biological chemistry. 278(36)
- Publication Year :
- 2003
-
Abstract
- Guanine nucleotide exchange factors (GEFs) and their associated GTP-binding proteins (G-proteins) are key regulatory elements in the signal transduction machinery that relays information from the extracellular environment into specific intracellular responses. Among them, the MAPK cascades represent ubiquitous downstream effector pathways. We have previously described that, analogous to the Ras-dependent activation of the Erk-1/2 pathway, members of the Rho family of small G-proteins activate the JNK cascade when GTP is loaded by their corresponding GEFs. Searching for novel regulators of JNK activity we have identified Epac (exchange protein activated by cAMP) as a strong activator of JNK-1. Epac is a member of a growing family of GEFs that specifically display exchange activity on the Rap subfamily of Ras small G-proteins. We report here that while Epac activates the JNK severalfold, a constitutively active (G12V) mutant of Rap1b does not, suggesting that Rap-GTP is not sufficient to transduce Epac-dependent JNK activation. Moreover, Epac signaling to the JNKs was not blocked by inactivation of endogenous Rap, suggesting that Rap activation is not necessary for this response. Consistent with these observations, domain deletion mutant analysis shows that the catalytic GEF domain is dispensable for Epac-mediated activation of JNK. These studies identified a region overlapping the Ras exchange motif domain as critical for JNK activation. Consistent with this, an isolated Ras exchange motif domain from Epac is sufficient to activate JNK. We conclude that Epac signals to the JNK cascade through a new mechanism that does not involve its canonical catalytic action, i.e. Rap-specific GDP/GTP exchange. This represents not only a novel way to activate the JNKs but also a yet undescribed mechanism of downstream signaling by Epac.
- Subjects :
- MAPK/ERK pathway
DNA, Complementary
Time Factors
GTP'
MAP Kinase Kinase 4
Mutant
Amino Acid Motifs
Blotting, Western
Biology
Transfection
Biochemistry
p38 Mitogen-Activated Protein Kinases
Cell Line
Guanine Nucleotide Exchange Factors
Humans
Molecular Biology
Genes, Dominant
Glutathione Transferase
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinase 3
Activator (genetics)
Effector
Gene Products, vpr
JNK Mitogen-Activated Protein Kinases
Cell Biology
DNA
Cell biology
Protein Structure, Tertiary
Enzyme Activation
Mutation
JNK cascade
Guanine nucleotide exchange factor
Signal transduction
Mitogen-Activated Protein Kinases
Gene Deletion
Plasmids
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 278
- Issue :
- 36
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry
- Accession number :
- edsair.doi.dedup.....6038aa54f59241239807e35e0a42888d