ArticleProceedings of the National Academy of Sciences of the United States of America2016
The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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37 citing papers in PubMed, 67 citations in OpenAlex.
- K-Ras controls asymmetric cell divisions from the primary cilium.Cell death & disease · 2026Article
- The impact of RAS on cell differentiation in health and disease.The Biochemical journal · 2025Review
- Neurofibromin Encoded by theInternational journal of molecular sciences · 2025Article
- Development of an adeno-associated virus vector for gene replacement therapy of NF1-related tumors.Nature communications · 2025Article
- Allosteric modulation of NF1 GAP: Differential distributions of catalytically competent populations in loss-of-function and gain-of-function mutants.Protein science : a publication of the Protein Society · 2025Article
- Global proteomics and affinity mass spectrometry analysis of human Schwann cells indicates that variation in and loss of neurofibromin (NF1) alters protein expression and cellular and mitochondrial metabolism.Scientific reports · 2025Article
- The therapeutic potential of neurofibromin signaling pathways and binding partners.Communications biology · 2023Review
- Neurofibromatosis Type 1: Pediatric Aspects and Review of Genotype-Phenotype Correlations.Cancers · 2023Review
- Functional Assays Combined with Pre-mRNA-Splicing Analysis Improve Variant Classification and Diagnostics for Individuals with Neurofibromatosis Type 1 and Legius Syndrome.Human mutation · 2023Article
- Mechanistic insights from animal models of neurofibromatosis type 1 cognitive impairment.Disease models & mechanisms · 2022Review
- Review
- Review
- RAS pathway regulation in melanoma.Disease models & mechanisms · 2022Review
- RAS and beyond: the many faces of the neurofibromatosis type 1 protein.Disease models & mechanisms · 2022Article
- The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1.Nature structural & molecular biology · 2021Article
- Article
- Article
- Accessory proteins of the RAS-MAPK pathway: moving from the side line to the front line.Communications biology · 2021Review
- Promotion of cancer cell stemness by Ras.Biochemical Society transactions · 2021Review
- SPRED proteins and their roles in signal transduction, development, and malignancy.Genes & development · 2020Review
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neurofibromatosis type 1 (NF1) and Legius syndrome are related diseases with partially overlapping symptoms caused by alterations of the tumor suppressor genes NF1 (encoding the protein neurofibromin) and SPRED1 (encoding sprouty-related, EVH1 domain-containing protein 1, Spred1), respectively. Both proteins are negative regulators of Ras/MAPK signaling with neurofibromin functioning as a Ras-specific GTPase activating protein (GAP) and Spred1 acting on hitherto undefined components of the pathway. Importantly, neurofibromin has been identified as a key protein in the development of cancer, as it is genetically altered in a large number of sporadic human malignancies unrelated to NF1. Spred1 has previously been demonstrated to interact with neurofibromin via its N-terminal Ena/VASP Homology 1 (EVH1) domain and to mediate membrane translocation of its target dependent on its C-terminal Sprouty domain. However, the region of neurofibromin required for the interaction with Spred1 has remained unclear. Here we show that the EVH1 domain of Spred1 binds to the noncatalytic (GAPex) portion of the GAP-related domain (GRD) of neurofibromin. Binding is compatible with simultaneous binding of Ras and does not interfere with GAP activity. Our study points to a potential targeting function of the GAPex subdomain of neurofibromin that is present in all known canonical RasGAPs.
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