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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 Raplb 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.

Registro:

Documento: Artículo
Título:Activation of JNK by Epac Is Independent of Its Activity as a Rap Guanine Nucleotide Exchanger
Autor:Hochbaum, D.; Tanos, T.; Ribeiro-Neto, F.; Altschulerll, D.; Coso, O.A.
Filiación:Depto. de Fisiol./Biol. Molec./Cel., Universidad de Buenos Aires, IFYBINE-CONICET, Buenos Aires 1428, Argentina
Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, United States
Department of Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States
Palabras clave:Catalysis; Cells; Proteins; Mutants; Biochemistry; guanine nucleotide exchange factor; Janus kinase; Rap protein; complementary DNA; DNA; glutathione transferase; guanine nucleotide exchange factor; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase kinase; mitogen activated protein kinase kinase 4; mitogen activated protein kinase p38; RAPGEF3 protein, human; stress activated protein kinase; Vpr protein; animal cell; article; catalysis; cell proliferation; deletion mutant; enzyme activation; enzyme activity; enzyme specificity; genetic analysis; nonhuman; priority journal; protein domain; protein family; protein stability; second messenger; signal transduction; cell line; dominant gene; enzyme activation; gene deletion; genetic transfection; human; metabolism; mutation; plasmid; protein binding; protein motif; protein tertiary structure; time; Western blotting; Animalia; Janus; Amino Acid Motifs; Blotting, Western; Cell Line; DNA; DNA, Complementary; Enzyme Activation; Gene Deletion; Gene Products, vpr; Genes, Dominant; Glutathione Transferase; Guanine Nucleotide Exchange Factors; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mutation; p38 Mitogen-Activated Protein Kinases; Plasmids; Protein Binding; Protein Structure, Tertiary; Signal Transduction; Time Factors; Transfection
Año:2003
Volumen:278
Número:36
Página de inicio:33738
Página de fin:33746
DOI: http://dx.doi.org/10.1074/jbc.M305208200
Título revista:Journal of Biological Chemistry
Título revista abreviado:J. Biol. Chem.
ISSN:00219258
CODEN:JBCHA
CAS:Janus kinase, 161384-16-3; DNA, 9007-49-2; glutathione transferase, 50812-37-8; mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; mitogen activated protein kinase kinase, 142805-58-1; mitogen activated protein kinase, 142243-02-5; stress activated protein kinase, 155215-87-5; DNA, 9007-49-2; DNA, Complementary; Gene Products, vpr; Glutathione Transferase, EC 2.5.1.18; Guanine Nucleotide Exchange Factors; JNK Mitogen-Activated Protein Kinases, EC 2.7.1.37; MAP Kinase Kinase 4, EC 2.7.1.-; Mitogen-Activated Protein Kinase 1, EC 2.7.1.37; Mitogen-Activated Protein Kinase 3, EC 2.7.1.37; Mitogen-Activated Protein Kinase Kinases, EC 2.7.1.-; Mitogen-Activated Protein Kinases, EC 2.7.1.37; p38 Mitogen-Activated Protein Kinases, EC 2.7.1.37; RAPGEF3 protein, human
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v278_n36_p33738_Hochbaum

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Citas:

---------- APA ----------
Hochbaum, D., Tanos, T., Ribeiro-Neto, F., Altschulerll, D. & Coso, O.A. (2003) . Activation of JNK by Epac Is Independent of Its Activity as a Rap Guanine Nucleotide Exchanger. Journal of Biological Chemistry, 278(36), 33738-33746.
http://dx.doi.org/10.1074/jbc.M305208200
---------- CHICAGO ----------
Hochbaum, D., Tanos, T., Ribeiro-Neto, F., Altschulerll, D., Coso, O.A. "Activation of JNK by Epac Is Independent of Its Activity as a Rap Guanine Nucleotide Exchanger" . Journal of Biological Chemistry 278, no. 36 (2003) : 33738-33746.
http://dx.doi.org/10.1074/jbc.M305208200
---------- MLA ----------
Hochbaum, D., Tanos, T., Ribeiro-Neto, F., Altschulerll, D., Coso, O.A. "Activation of JNK by Epac Is Independent of Its Activity as a Rap Guanine Nucleotide Exchanger" . Journal of Biological Chemistry, vol. 278, no. 36, 2003, pp. 33738-33746.
http://dx.doi.org/10.1074/jbc.M305208200
---------- VANCOUVER ----------
Hochbaum, D., Tanos, T., Ribeiro-Neto, F., Altschulerll, D., Coso, O.A. Activation of JNK by Epac Is Independent of Its Activity as a Rap Guanine Nucleotide Exchanger. J. Biol. Chem. 2003;278(36):33738-33746.
http://dx.doi.org/10.1074/jbc.M305208200