RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3
| Autor: | Anne-Françoise Burnol, Katia Cailliau, Edith Browaeys-Poly, Arlette Lescuyer, Christian Widmann, Álvaro Cuesta-Marbán |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
Cell signaling Microinjections Recombinant Fusion Proteins Primary Cell Culture Mechanistic Target of Rapamycin Complex 2 Biology Biochemistry Xenopus laevis Cell Line Tumor Phosphoprotein Phosphatases Animals Humans Enzyme Inhibitors Phosphorylation Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Mitogen-Activated Protein Kinase 1 PHLPP Caspase 3 TOR Serine-Threonine Kinases fungi Ovary Nuclear Proteins p120 GTPase Activating Protein Cell Biology Peptide Fragments Cell biology Protein Structure Tertiary G2 Phase Cell Cycle Checkpoints Gene Expression Regulation Fibroblast growth factor receptor Multiprotein Complexes Proteolysis Oocytes Fibroblast Growth Factor 1 Female Signal transduction Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Journal of Biological Chemistry, vol. 290, no. 32, pp. 19653-19665 Journal of Biological Chemistry |
| Popis: | Fibroblast growth factor receptors (FGFRs) are involved in proliferative and differentiation physiological responses. Deregulation of FGFR-mediated signaling involving the Ras/PI3K/Akt and the Ras/Raf/ERK MAPK pathways is causally involved in the development of several cancers. The caspase-3/p120 RasGAP module is a stress sensor switch. Under mild stress conditions, RasGAP is cleaved by caspase-3 at position 455. The resulting N-terminal fragment, called fragment N, stimulates anti-death signaling. When caspase-3 activity further increases, fragment N is cleaved at position 157. This generates a fragment, called N2, that no longer protects cells. Here, we investigated in Xenopus oocytes the impact of RasGAP and its fragments on FGF1-mediated signaling during G2/M cell cycle transition. RasGAP used its N-terminal Src homology 2 domain to bind FGFR once stimulated by FGF1, and this was necessary for the recruitment of Akt to the FGFR complex. Fragment N, which did not associate with the FGFR complex, favored FGF1-induced ERK stimulation, leading to accelerated G2/M transition. In contrast, fragment N2 bound the FGFR, and this inhibited mTORC2-dependent Akt Ser-473 phosphorylation and ERK2 phosphorylation but not phosphorylation of Akt on Thr-308. This also blocked cell cycle progression. Inhibition of Akt Ser-473 phosphorylation and entry into G2/M was relieved by PHLPP phosphatase inhibition. Hence, full-length RasGAP favors Akt activity by shielding it from deactivating phosphatases. This shielding was abrogated by fragment N2. These results highlight the role played by RasGAP in FGFR signaling and how graded stress intensities, by generating different RasGAP fragments, can positively or negatively impact this signaling. |
| Databáze: | OpenAIRE |
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