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Published on: April 22, 2021
NF1 and SPRED1/2 cooperate through RAS-MAPK-independent functions
Jillian M Silva1, Lizzeth Canche1, Alice Cheng1
1Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94153.
Summary
Neurofibromin (NF1) and SPRED proteins regulate RAS-MAPK signaling independently of RAS. Their cooperation controls gene expression and impacts Neurofibromatosis type I patient cells, revealing novel therapeutic targets.
Area of Science:
- Molecular Biology
- Cell Signaling
- Genetics
Background:
- Neurofibromin (NF1) negatively regulates the RAS-MAPK pathway through interaction with SPRED proteins.
- While NF1's RAS GTPase-stimulating domain is known, other NF1 functions remain unclear.
- The interplay between NF1 and SPRED1/2 in RAS-independent signaling requires further investigation.
Purpose of the Study:
- To investigate the RAS-independent functions of NF1 and SPRED1/2.
- To elucidate the cooperative mechanisms of NF1 and SPRED1/2 in cellular signaling.
- To identify NF1-SPRED1/2-dependent gene signatures and their regulation.
Main Methods:
- CRISPR-Cas9 gene editing in "RASless" mouse embryonic fibroblast (MEF) cell lines.
- Utilized KRAS4b wild-type and oncogenic KRAS variants.
- Transcriptome microarray analysis and validation in patient-derived Schwann cells.
Main Results:
- Loss of SPRED1/2 phenocopied NF1 loss, highlighting their cooperative role in modulating MAPK-AKT signaling.
- NF1 or SPRED1/2 loss suppressed RRAS and RRAS2 GTPases independently of RAS or AKT activation.
- Identified specific RAS-independent gene signatures regulated by NF1-SPRED1/2 cooperation, also influenced by NF1's RAS-GTPase function.
Conclusions:
- NF1 and SPRED1/2 cooperate to regulate RAS-independent signaling pathways.
- This cooperation is uncoupled from canonical MAPK signaling and influences specific gene expression.
- Findings provide insights into NF1's multifaceted roles beyond RAS regulation and potential therapeutic strategies for Neurofibromatosis type I.
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