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RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once
Katia Cailliau1, Arlette Lescuyer2, Anne-Françoise Burnol3
1From the Université de Lille 1, Sciences et Technologies, Team Signal Division Regulation, CNRS UMR 8576, SN3, 59655 Villeneuve d'Ascq Cedex, France, katia.maggio@univ-lille1.fr.
Abstract:
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.
Insights
Cellular stress generates RasGAP fragments that differentially regulate Fibroblast Growth Factor Receptor (FGFR) signaling. These fragments control cell cycle progression by modulating Akt and ERK pathways, impacting cancer development.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Fibroblast growth factor receptors (FGFRs) mediate critical cellular processes like proliferation and differentiation.
- Aberrant FGFR signaling, involving Ras/PI3K/Akt and Ras/Raf/ERK pathways, contributes to cancer development.
- The p120 RasGAP protein acts as a stress sensor, undergoing caspase-3 cleavage into fragments with distinct signaling roles.
Purpose of the Study:
- To investigate the role of RasGAP and its fragments in modulating Fibroblast Growth Factor 1 (FGF1)-mediated signaling during the G2/M cell cycle transition in Xenopus oocytes.
- To elucidate how different RasGAP fragments influence key signaling pathways like Akt and ERK in response to FGF1 stimulation.
- To understand the impact of stress-induced RasGAP cleavage on cell cycle progression.
Main Methods:
- Utilized Xenopus oocytes as a model system to study FGF1 signaling.
- Investigated the interaction of RasGAP and its fragments (N and N2) with FGFR and downstream signaling components.
- Assessed the phosphorylation status of Akt and ERK, and monitored cell cycle progression.
- Examined the effect of PHLPP phosphatase inhibition on signaling pathways.
Main Results:
- Full-length RasGAP recruits Akt to FGFR, promoting its activity and shielding it from phosphatases.
- Fragment N, generated under mild stress, enhances FGF1-induced ERK signaling, accelerating G2/M transition.
- Fragment N2, from increased stress, binds FGFR, inhibits mTORC2-dependent Akt phosphorylation, and blocks cell cycle progression.
- Inhibition of Akt Ser-473 phosphorylation by N2 can be rescued by PHLPP inhibition.
Conclusions:
- RasGAP plays a crucial role in fine-tuning FGFR signaling pathways.
- The graded cleavage of RasGAP by caspase-3 acts as a switch, with different fragments mediating opposing effects on cell cycle progression.
- Understanding RasGAP's role in FGFR signaling provides insights into cancer development and potential therapeutic strategies.
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