Epac, in synergy with cAMP-dependent protein kinase (PKA), is required for cAMP-mediated mitogenesis
| Autor: | Kyoungja Hong, Daniel Hochbaum, Guillermo Barila, Daniel L. Altschuler, Fernando Ribeiro-Neto |
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| Rok vydání: | 2007 |
| Předmět: |
Thyrotropin
Biochemistry Cell Line Cyclic AMP Animals Guanine Nucleotide Exchange Factors Phosphorylation Protein kinase A Molecular Biology Cell Proliferation DNA synthesis Chemistry Cell growth Activator (genetics) rap1 GTP-Binding Proteins Cell Biology DNA Subcellular localization Cyclic AMP-Dependent Protein Kinases Cell biology Protein Structure Tertiary Rats Enzyme Activation Protein Transport DEP domain Mutation Cancer research Rap1 Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 283(8) |
| ISSN: | 0021-9258 |
| Popis: | cAMP stimulates proliferation in many cell types. For many years, cAMP-dependent protein kinase (PKA) represented the only known cAMP effector. PKA, however, does not fully mimic the action of cAMP, indicating the existence of a PKA-independent component. Since cAMP-mediated activation of the G-protein Rap1 and its phosphorylation by PKA are strictly required for the effects of cAMP on mitogenesis, we hypothesized that the Rap1 activator Epac might represent the PKA-independent factor. Here we report that Epac acts synergistically with PKA in cAMP-mediated mitogenesis. We have generated a new dominant negative Epac mutant that revealed that activation of Epac is required for thyroid-stimulating hormone or cAMP stimulation of DNA synthesis. We demonstrate that Epac's action on cAMP-mediated activation of Rap1 and cAMP-mediated mitogenesis depends on the subcellular localization of Epac via its DEP domain. Disruption of the DEP-dependent subcellular targeting of Epac abolished cAMP-Epac-mediated Rap1 activation and thyroid-stimulating hormone-mediated cell proliferation, indicating that an Epac-Rap-PKA signaling unit is critical for the mitogenic action of cAMP. |
| Databáze: | OpenAIRE |
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