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Cited by 86Neurofibromatosis and Schwannoma CasesProtein Tyrosine PhosphatasesNeuroblastoma Research and Treatments

RAS and beyond: the many faces of the neurofibromatosis type 1 protein

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Anastasaki, Corina, Orozco, Paola, Gutmann, David H.·2022·Disease Models & Mechanisms
DOI 10.1242/dmm.049362PMC PMC8891636
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Abstract

Neurofibromatosis type 1 is a rare neurogenetic syndrome, characterized by pigmentary abnormalities, learning and social deficits, and a predisposition for benign and malignant tumor formation caused by germline mutations in the NF1 gene. With the cloning of the NF1 gene and the recognition that the encoded protein, neurofibromin, largely functions as a negative regulator of RAS activity, attention has mainly focused on RAS and canonical RAS effector pathway signaling relevant to disease pathogenesis and treatment. However, as neurofibromin is a large cytoplasmic protein the RAS regulatory domain of which occupies only 10% of its entire coding sequence, both canonical and non-canonical RAS pathway modulation, as well as the existence of potential non-RAS functions, are becoming apparent. In this Special article, we discuss our current understanding of neurofibromin function.

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  • Loss of the GAP NF1 can act as a resistance mechanism for KRAS inhibition, suggesting that NF1 may have KRAS-independent functions.

    “The intrinsic hydrolysis rate of G12C is inherently high; hence, the fact that the loss of the GAP NF1 can act as a resistance mechanism for KRAS inhibition suggests that NF1 may have KRAS-independent functions [4,56,111].”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [111]

    The Introduction identifies NF1’s neurofibromin protein as a GAP that regulates KRAS, and the ‘RAS-independent neurofibromin function’ section describes functions beyond RAS signaling (page numbers unavailable). The paper does not report that NF1 loss causes resistance to KRAS inhibition or connect such resistance to those independent functions. (LLM, conf=0.85)

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Authors
Anastasaki, C., Orozco, P., & Gutmann, D. H.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Anastasaki, Corina
ORCID
Venue
Disease Models & Mechanisms
Publisher
The Company of Biologists
Published
2022-02-01
Volume
15
Issue
2
ISSN
  • 1754-8403 (ISSN-L)
  • 1754-8411
DOI
10.1242/dmm.049362
PMC
PMC8891636
OpenAlex
W4213050171
Cited by
86
References
145
Citations by year
2026: 24 · 2025: 27 · 2024: 23 · 2023: 8 · 2022: 4
FWCI
8.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Disease Models & Mechanisms (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Cancer Institute (1R50CA233164)
  • National Institute of Neurological Disorders and Stroke (1R35NS097211)
  • Alvin J. Siteman Cancer Center
Topics
  • Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
Keywords
neurofibromatosis type 1, neurofibromin, NF1 gene, Ras signaling, Ras effector pathways, tumor suppressor function, germline mutations
MeSH terms
Humans, Neurofibromatosis 1, Proteins, Signal Transduction, Genes, Neurofibromatosis 1, Neurofibromin 1

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