ArticleThe Journal of biological chemistry2016
Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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39 citing papers in PubMed, 66 citations in OpenAlex.
- Article
- Development of an adeno-associated virus vector for gene replacement therapy of NF1-related tumors.Nature communications · 2025Article
- Unraveling novel variants in the NF1 gene and investigating potential therapeutic strategies.Scientific reports · 2025Article
- Review
- 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
- A Novel Homozygous Loss-of-Function Variant inGenes · 2023Article
- 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
- The molecular genetics of RASopathies: An update on novel disease genes and new disorders.American journal of medical genetics. Part C, Seminars in medical genetics · 2022Review
- Identification of Germinal Neurofibromin Hotspots.Biomedicines · 2022Article
- Targeted exon skipping ofMolecular therapy. Nucleic acids · 2022Article
- Review
- RAS pathway regulation in melanoma.Disease models & mechanisms · 2022Review
- SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype.American journal of human genetics · 2021Article
- Review
- MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders.Molecular autism · 2021Article
- SPRED1 deletion confers resistance to MAPK inhibition in melanoma.The Journal of experimental medicine · 2021Article
- SOCS, SPRED, and NR4a: Negative regulators of cytokine signaling and transcription in immune tolerance.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2021Article
- SPRED proteins and their roles in signal transduction, development, and malignancy.Genes & development · 2020Review
- Review
- Genetic basis of neurofibromatosis type 1 and related conditions, including mosaicism.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2020Article
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Authors and funding
11 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius syndrome, which consists of symptoms of multiple café-au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing α-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120(GAP). Several mutations in these N- and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome.
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