GLP-1 Mediates Antiapoptotic Effect by Phosphorylating Bad through a β-Arrestin 1-mediated ERK1/2 Activation in Pancreatic β-Cells
| Autor: | Stéphane Dalle, Elodie M. Varin, Christine Longuet, Gyslaine Bertrand, Safia Costes, Joël Bockaert, Nathalie Linck, Julie Quoyer, Christophe Broca |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Scaffold protein
Time Factors Gs alpha subunit Arrestins Mitogen-Activated Protein Kinase 3 Apoptosis Biology Ribosomal Protein S6 Kinases 90-kDa Biochemistry Cell Line Mice Cytosol Glucagon-Like Peptide 1 Insulin-Secreting Cells Cyclic AMP Serine Animals Phosphorylation Protein kinase A Molecular Biology beta-Arrestins Mitogen-Activated Protein Kinase 1 Beta-Arrestins Kinase Mechanisms of Signal Transduction Cell Biology Cyclic AMP-Dependent Protein Kinases Cell biology Enzyme Activation beta-Arrestin 1 14-3-3 Proteins bcl-Associated Death Protein Signal transduction Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 285:1989-2002 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m109.067207 |
| Popis: | Strategies based on activating GLP-1 receptor (GLP-1R) are intensively developed for the treatment of type 2 diabetes. The exhaustive knowledge of the signaling pathways linked to activated GLP-1R within the beta-cells is of major importance. In beta-cells, GLP-1 activates the ERK1/2 cascade by diverse pathways dependent on either Galpha(s)/cAMP/cAMP-dependent protein kinase (PKA) or beta-arrestin 1, a scaffold protein. Using pharmacological inhibitors, beta-arrestin 1 small interfering RNA, and islets isolated from beta-arrestin 1 knock-out mice, we demonstrate that GLP-1 stimulates ERK1/2 by two temporally distinct pathways. The PKA-dependent pathway mediates rapid and transient ERK1/2 phosphorylation that leads to nuclear translocation of the activated kinases. In contrast, the beta-arrestin 1-dependent pathway produces a late ERK1/2 activity that is restricted to the beta-cell cytoplasm. We further observe that GLP-1 phosphorylates the cytoplasmic proapoptotic protein Bad at Ser-112 but not at Ser-155. We find that the beta-arrestin 1-dependent ERK1/2 activation engaged by GLP-1 mediates the Ser-112 phosphorylation of Bad, through p90RSK activation, allowing the association of Bad with the scaffold protein 14-3-3, leading to its inactivation. beta-Arrestin 1 is further found to mediate the antiapoptotic effect of GLP-1 in beta-cells through the ERK1/2-p90RSK-phosphorylation of Bad. This new regulatory mechanism engaged by activated GLP-1R involving a beta-arrestin 1-dependent spatiotemporal regulation of the ERK1/2-p90RSK activity is now suspected to participate in the protection of beta-cells against apoptosis. Such signaling mechanism may serve as a prototype to generate new therapeutic GLP-1R ligands. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|