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Feedback activation of neurofibromin terminates growth factor-induced Ras activation
- Source :
- Cell communication and signaling, 14:5, Cell Communication and Signaling : CCS
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
Abstract
- Background Growth factors induce a characteristically short-lived Ras activation in cells emerging from quiescence. Extensive work has shown that transient as opposed to sustained Ras activation is critical for the induction of mitogenic programs. Mitogen-induced accumulation of active Ras-GTP results from increased nucleotide exchange driven by the nucleotide exchange factor Sos. In contrast, the mechanism accounting for signal termination and prompt restoration of basal Ras-GTP levels is unclear, but has been inferred to involve feedback inhibition of Sos. Remarkably, how GTP-hydrolase activating proteins (GAPs) participate in controlling the rise and fall of Ras-GTP levels is unknown. Results Monitoring nucleotide exchange of Ras in permeabilized cells we find, unexpectedly, that the decline of growth factor-induced Ras-GTP levels proceeds in the presence of unabated high nucleotide exchange, pointing to GAP activation as a major mechanism of signal termination. Experiments with non-hydrolysable GTP analogues and mathematical modeling confirmed and rationalized the presence of high GAP activity as Ras-GTP levels decline in a background of high nucleotide exchange. Using pharmacological and genetic approaches we document a raised activity of the neurofibromatosis type I tumor suppressor Ras-GAP neurofibromin and an involvement of Rsk1 and Rsk2 in the down-regulation of Ras-GTP levels. Conclusions Our findings show that, in addition to feedback inhibition of Sos, feedback stimulation of the RasGAP neurofibromin enforces termination of the Ras signal in the context of growth-factor signaling. These findings ascribe a precise role to neurofibromin in growth factor-dependent control of Ras activity and illustrate how, by engaging Ras-GAP activity, mitogen-challenged cells play safe to ensure a timely termination of the Ras signal irrespectively of the reigning rate of nucleotide exchange. Electronic supplementary material The online version of this article (doi:10.1186/s12964-016-0128-z) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Son of Sevenless Protein, Drosophila
MAP Kinase Signaling System
medicine.medical_treatment
Context (language use)
Biochemistry
Ribosomal Protein S6 Kinases, 90-kDa
Cell Line
Nucleotide exchange factor
03 medical and health sciences
Mice
Epidermal growth factor
medicine
Animals
Humans
GEF
Phosphorylation
Molecular Biology
Neurofibromin 1
biology
Epidermal Growth Factor
Research
Rsk
Growth factor
HEK 293 cells
GAP
Neurofibromin
Cell Biology
Cell biology
Enzyme Activation
030104 developmental biology
HEK293 Cells
NF1
biology.protein
ras Proteins
Guanosine Triphosphate
Signal transduction
Ras
HeLa Cells
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cell communication and signaling, 14:5, Cell Communication and Signaling : CCS
- Accession number :
- edsair.doi.dedup.....d2cf16eb37d7d65e76f669c4604fb62e