ArticleCell communication and signaling : CCS2016
Feedback activation of neurofibromin terminates growth factor-induced Ras activation.
Article in Cell communication and signaling : CCS, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 35 citations in OpenAlex.
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- Splicing is an alternate oncogenic pathway activation mechanism in glioma.Nature communications · 2022Article
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- Identification of transcription factors and construction of a novel miRNA regulatory network in primary osteoarthritis by integrated analysis.BMC musculoskeletal disorders · 2021Article
- Blockade of Serotonin 5-HTInternational journal of molecular sciences · 2021Article
- Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Active GTPase Pulldown Protocol.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Anchorage-independent growth conditions reveal a differential SOS2 dependence for transformation and survival inSmall GTPases · 2021Article
- Regulation of the Small GTPase Ras and Its Relevance to Human Disease.Methods in molecular biology (Clifton, N.J.) · 2021Review
- Review
- Characterisation of HRas local signal transduction networks using engineered site-specific exchange factors.Small GTPases · 2020Article
- Review
- Role of ALDH1A1 and HTRA2 expression in CCL2/CCR2-mediated breast cancer cell growth and invasion.Biology open · 2019Article
- New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling.Seminars in cancer biology · 2019Review
- BRAF fusions identified in melanomas have variable treatment responses and phenotypes.Oncogene · 2019Article
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundGrowth 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.
resultsMonitoring 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.
conclusionsOur 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.