Affinage

NF1

Neurofibromin · UniProt P21359

Length
2839 aa
Mass
319.4 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Neurofibromin (NF1) is a tumor-suppressor GTPase-activating protein whose central activity is to accelerate hydrolysis of RAS-GTP, thereby restraining downstream RAS effector cascades that govern cell proliferation, differentiation, and survival (PMID:9003501, PMID:15467460). GTPase-activating activity is encoded by the GAP-related domain (exons 20–27a), where the R1391S substitution reduces catalytic activity ~300-fold (PMID:9003501). Despite sharing in vitro GTPase-activating properties with p120-GAP, neurofibromin exerts distinct biological effects on RAS-driven transcription in cells (PMID:8455625). Full-length neurofibromin functions as a high-affinity dimer, and the N- and C-terminal halves reconstitute dimer-like, GTPase-active structures when co-expressed (PMID:31836666); patient variants clustered at the dimerization interface (codons 844–848 and others predicted from the cryo-EM structure) destabilize and dominantly inactivate wild-type protein, providing a structural basis for genotype–phenotype correlation (PMID:36689660). Through control of RAS, neurofibromin loss deregulates both ERK/MAPK and PI3K/mTOR arms: it antagonizes cAMP accumulation and cyclin D1 to limit Schwann cell proliferation (PMID:11160381), suppresses BRAF-induced senescence via combined PI3K and ERK deregulation (PMID:23171796), and gates RAS-ERK attenuation downstream of mutant EGFR to set drug sensitivity in lung cancer (PMID:24535670). In the nervous system, neurofibromin couples RAS to cAMP homeostasis through an atypical PKC-ζ→GRK2→Gαs route independent of MEK/AKT (PMID:25070947), restrains MAPK/PAK1 signaling underlying GABAergic and synaptic deficits (PMID:25242307), maintains oligodendrocyte myelin through suppression of Notch (PMID:28423318), and regulates nociceptive ion channels by sequestering CRMP2 away from syntaxin 1A and CaV2.2 (PMID:29655575). Neurofibroma genesis requires cell-autonomous NF1 loss in the Schwann cell/neural-precursor lineage together with a haploinsufficient microenvironment, in which mast cells signaling through c-kit and bone marrow–derived cells acting via GM-CSF are essential contributors (PMID:11988578, PMID:18984156, PMID:10678181). Germline NF1 loss in this disease also drives optic glioma through neuronal-activity–dependent NLGN3 shedding (PMID:34040258). NF1 is the gene underlying neurofibromatosis type 1, in which distinct germline mutations confer distinct cell-autonomous and stromal tumor phenotypes (PMID:26908603).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1993 Medium

    Established that neurofibromin, although a RAS-GAP, produces biological effects distinct from the canonical p120-GAP, implying a dedicated regulatory role rather than redundancy.

    Evidence Microinjection of purified type I NF1 vs. GAP into fibroblasts with AP-1 reporter and DNA-synthesis readouts

    PMID:8455625

    Open questions at the time
    • Did not map the domain responsible
    • Single lab, indirect readouts of RAS output
  2. 1995 High

    Localized and quantified the catalytic GAP function to the GRD and demonstrated that a single missense mutation cripples activity, linking enzymatic loss to disease-associated variants.

    Evidence Site-directed mutagenesis (R1391S), in vitro expression, and direct GAP activity assay

    PMID:9003501

    Open questions at the time
    • Does not address full-length regulation outside the GRD
    • No structural mechanism for the activity loss
  3. 1995 Medium

    Revealed isoform-specific and developmentally regulated forms of neurofibromin (type 1 vs type 2, exon 23a) with differing microtubule association, indicating non-GAP functional diversification.

    Evidence Northern/Western blot, in situ hybridization, and microtubule co-fractionation across tissues and mouse embryos

    PMID:7568895 PMID:7794799

    Open questions at the time
    • Functional consequence of microtubule binding undefined
    • No mechanism linking isoform to RAS activity
  4. 2000 High

    Defined GM-CSF signaling as a required driver of Nf1-deficient myeloproliferation, establishing cytokine dependence of hematopoietic NF1 phenotypes.

    Evidence Nf1;Gmcsf double-knockout intercross with adoptive transfer and colony assays

    PMID:10678181

    Open questions at the time
    • Did not connect to solid-tumor microenvironment
    • Mechanism of GM-CSF hypersensitivity at the receptor level not resolved
  5. 2001 High

    Placed cyclin D1 and cAMP downstream of Nf1 in Schwann cell growth control, identifying a concrete cell-cycle effector of neurofibromin loss.

    Evidence Inducible cyclin D1 retroviral expression, cAMP and BrdU assays in Nf1-/- vs WT Schwann cells

    PMID:11160381

    Open questions at the time
    • Link from RAS to cAMP not yet mechanistically defined
    • Restricted to Schwann cell lineage
  6. 2002 High

    Demonstrated that Schwann cell-autonomous NF1 loss plus a heterozygous microenvironment is the combination required for neurofibroma formation, defining a two-compartment tumor model.

    Evidence Krox20-Cre conditional Nf1 knockout on Nf1+/- background with tumor histology

    PMID:11988578

    Open questions at the time
    • Identity of the contributing stromal cell type unknown
    • Microenvironmental signals not yet defined
  7. 2006 Medium

    Showed NF1 expression is subject to CTCF-dependent long-range interchromosomal regulation, adding a transcriptional control layer.

    Evidence 3C, FISH, CTCF knockdown and ICR-deletion mouse with Wsb1/Nf1 expression analysis

    PMID:16614224

    Open questions at the time
    • Relevance to human NF1 disease unestablished
    • Single-locus mechanism, magnitude of expression effect modest
  8. 2008 High

    Identified mast cells, c-kit signaling, and an EGFR-dependent nerve progenitor pool as the cellular and receptor mediators of the neurofibroma microenvironment and cell of origin.

    Evidence Bone marrow transplantation, c-kit intercross, imatinib, DhhCre conditional KO, sphere assays, and human EGFR+/P75+ cell xenografts

    PMID:18984156 PMID:19041782

    Open questions at the time
    • Quantitative contribution of each compartment unclear
    • How NF1-null Schwann cells recruit mast cells not yet defined
  9. 2009 Medium

    Identified skin-derived precursors as the cell of origin for dermal neurofibromas, refining the lineage in which NF1 loss initiates tumors.

    Evidence P0-Cre conditional Nf1 loss in SKPs with lineage tracing and transplantation

    PMID:19427294

    Open questions at the time
    • Microenvironmental signals defined only as 'additional'
    • Relation to plexiform neurofibroma origin not addressed
  10. 2010 Medium

    Connected NF1 loss to mTOR survival dependency in AML and defined the SCF/Kit ligand–PI3K axis by which Nf1-/- Schwann cells provoke mast cell degranulation.

    Evidence Ras-GTP pulldown, shRNA, rapamycin sensitivity in AML blasts; conditioned-medium degranulation with Nf1/PI3K intercrosses

    PMID:20505189 PMID:21037083

    Open questions at the time
    • mTOR dependency tested ex vivo only
    • Whether SCF-PI3K loop is generalizable across tumor stages unclear
  11. 2011 Medium

    Showed that timing and Schwann cell subtype of NF1 loss dictate neurofibroma onset and size, and confirmed non-cell-autonomous lympho-hematopoietic expansion.

    Evidence Tamoxifen-inducible PlpCre;Nf1fl/fl with EGFP lineage tracing across perinatal vs adult induction

    PMID:21551249

    Open questions at the time
    • Molecular basis of differing tumor kinetics unresolved
    • Why GFAP+ non-myelinating cells are exempt unknown
  12. 2012 High

    Established NF1 as a cooperating tumor suppressor in melanoma that prevents oncogene-induced senescence and sets BRAF-inhibitor sensitivity through dual PI3K/ERK control.

    Evidence BRAF+Nf1 mouse model, senescence and proliferation assays, pathway biochemistry, BRAF-inhibitor sensitivity in cell lines

    PMID:23171796

    Open questions at the time
    • Relative weighting of PI3K vs ERK contribution unresolved
    • Does not address other sporadic cancer contexts
  13. 2013 Medium

    Extended neurofibromin function beyond tumor suppression into muscle energy metabolism and vascular neointima formation via Ras-Erk in macrophages.

    Evidence Muscle-specific Nf1 KO with metabolic/enzymatic assays; Nf1+/- carotid injury model with MEK-inhibitor rescue

    PMID:24163128 PMID:24211110

    Open questions at the time
    • Direct RAS substrate link in muscle metabolism not shown
    • Cell-autonomous vs systemic metabolic effects not separated
  14. 2014 High

    Resolved neuron-specific and tumor-specific effector branches: a RAS→PKC-ζ→GRK2→Gαs cAMP route, a MAPK/PAK1 synaptic axis, and a RAS-MAPK→MAF→mTOR crosstalk in MPNST; also defined NF1 control of EGFR-driven RAS-ERK attenuation.

    Evidence iPSC neural progenitors and Nf1 mice (cAMP); Pak1 KO/inhibitor amygdala rescue; MAF/DEPTOR overexpression with RAD001; genome-wide siRNA screen with MEK-inhibitor rescue

    PMID:24509877 PMID:24535670 PMID:25070947 PMID:25242307

    Open questions at the time
    • How a single GAP selects distinct effector branches across cell types unknown
    • MAF transcriptional targets only partially mapped
  15. 2016 High

    Demonstrated that the specific germline NF1 mutation, via differing residual protein levels, determines both cell-autonomous proliferation and stromal glioma phenotype.

    Evidence Patient-derived R681X vs G848R knock-in mice with optic nerve, microglia, and astrocyte readouts

    PMID:26908603

    Open questions at the time
    • Mechanism linking residual neurofibromin level to microglial activation incomplete
    • Generalizability to other variants untested here
  16. 2017 High

    Identified Notch and Wnt/β-catenin as tissue-specific downstream effectors of neurofibromin in oligodendrocyte myelin maintenance and fracture repair.

    Evidence Oligodendrocyte-specific Nf1 KO with γ-secretase/MEK/NOS inhibitor rescue and patient tissue; Nf1-/- fracture model with β-catenin readouts and Nefopam rescue

    PMID:28254468 PMID:28423318

    Open questions at the time
    • Direct biochemical link from RAS to Notch/β-catenin not established
    • Whether effects are GAP-dependent untested
  17. 2018 High

    Established a non-canonical neurofibromin function in pain signaling through CRMP2 sequestration controlling NaV1.7/CaV2.2 and CGRP release.

    Evidence Co-IP network, CRISPR Nf1 editing, electrophysiology, CGRP release, and CNRP1 peptide rescue with behavior

    PMID:29655575

    Open questions at the time
    • Whether CRMP2 interaction is GAP-domain dependent unclear
    • Human translation of CNRP1 rescue not addressed
  18. 2019 High

    Determined that full-length neurofibromin is an obligate high-affinity dimer reconstitutable from N- and C-terminal halves, defining its quaternary structure and a route to GTPase activation.

    Evidence SEC-MALS, SAXS/SANS, AUC, negative-stain EM, in vitro GTPase assay, and fragment reconstitution in cells

    PMID:31836666

    Open questions at the time
    • Atomic-resolution interface not yet defined at this stage
    • Regulatory role of dimerization in vivo unaddressed
  19. 2021 High

    Showed that NF1-driven optic glioma requires neuronal-activity–dependent NLGN3 shedding, defining an obligate non-cell-autonomous initiation mechanism.

    Evidence Nf1 OPG mouse model with light deprivation, Nlgn3 KO, and ADAM10 shedding-inhibitor rescue plus MRI tumor quantification

    PMID:34040258

    Open questions at the time
    • Link from neurofibromin loss to NLGN3 shedding sensitization not fully mechanistic
    • Restricted to optic pathway gliomas
  20. 2023 High

    Provided a cryo-EM structural basis for dominant-negative NF1 variants that destabilize wild-type neurofibromin via the dimer interface, enabling variant prediction.

    Evidence Cryo-EM structure, codon 844–848 variant stability assays, Co-IP, and computational prediction with experimental validation

    PMID:36689660

    Open questions at the time
    • Clinical penetrance of predicted variants not established
    • Functional consequence on RAS output in patient cells not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single dimeric RAS-GAP selects among its distinct cell-type-specific effector branches (cAMP/PKC-ζ, Notch, β-catenin, CRMP2, MAF-mTOR) and how dimerization is dynamically regulated in vivo remain unresolved.
  • No unifying mechanism linking GAP activity to non-RAS effector engagement
  • Regulation of dimer assembly/disassembly in cells unknown
  • Whether non-GAP functions require dimerization untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0140313 molecular sequestering activity 1
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3
Partners
CACNA2 (CAV2.2)CRMP2STX1A
Complex memberships
neurofibromin homodimer

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Full-length type I NF1 (neurofibromin) coinjected with wild-type Ras abolished Ras-induced AP-1 reporter gene expression in fibroblasts, whereas type II GAP did not; serum-stimulated DNA synthesis was reduced by type I GAP but not by type I NF1, demonstrating that NF1 and GAP have distinct in vivo biological activities despite similar in vitro GTPase-activating properties toward Ras. Microinjection of purified proteins into fibroblasts, AP-1-controlled reporter gene assay, DNA synthesis measurement Molecular and cellular biology Medium 8455625
1995 The GAP-related domain (GRD) of neurofibromin encoded by exons 20–27a is required for GTPase-activating activity toward Ras; the missense mutation R1391S in the GRD reduces GAP activity approximately 300-fold compared to wild-type NF1 GRD, as measured by in vitro GAP assay after site-directed mutagenesis and expression. Site-directed mutagenesis, in vitro expression, GAP activity assay Human genetics High 9003501
1995 NF1 type 1 and type 2 isoforms (differing by the 21-amino-acid exon 23a insertion) are differentially expressed: type 1 predominates in CNS neurons and is associated with microtubule binding, while type 2 predominates in glial cells and during early embryogenesis; type 2 neurofibromin does not associate with brain cytoplasmic microtubules in the same fashion as type 1, suggesting isoform-specific functional differences. Northern blot, in situ hybridization, Western blot analysis of tissue fractions, microtubule co-fractionation assay Cell growth & differentiation Medium 7794799
1995 During mouse embryogenesis, type 2 NF1 mRNA predominates before embryonic day 10, after which type 1 NF1 mRNA becomes predominant; type 2 neurofibromin is not associated with cytoplasmic microtubules in brain in the same fashion as type 1, suggesting the developmental isoform switch has functional consequences for microtubule interaction. Northern blot, Western blot, cytoplasmic microtubule co-fractionation in mouse brain Progress in brain research Medium 7568895
1996 Neurofibromin expression is upregulated in reactive astrocytes in response to cerebral ischemia (both focal and global models in rats), co-incident with GFAP upregulation, indicating a role for neurofibromin in injury-induced growth regulatory pathways in astrocytes. Immunohistochemistry in rat focal and global ischemia models, Western blot Journal of neuroscience research Low 8820972
1996 The NF1 alternative splicing of exons 23a/23b in the GRD region can be modulated by extrinsic factors in PC12 cells: nerve growth factor and dexamethasone increase the type I isoform concurrent with decreased proliferation; cycloheximide treatment reveals an additional transcript (type III). Dexamethasone effect is RNA-synthesis-dependent. RT-PCR isoform analysis in PC12 cells with pharmacological treatments (NGF, dexamethasone, cycloheximide), actinomycin D block Experimental cell research Low 8892969
2000 GM-CSF plays a central role in establishing and maintaining the myeloproliferative disorder (MPD) driven by Nf1 deficiency: hematopoietic cells doubly deficient in Nf1 and Gmcsf fail to induce MPD in recipients, but remain hypersensitive to exogenous GM-CSF, demonstrating that Nf1-deficient myeloid cells require GM-CSF signaling for their excessive proliferation in vivo. Genetic intercross of Nf1 and Gmcsf knockout mice, adoptive transfer of fetal liver hematopoietic cells, methylcellulose colony assay, exogenous GM-CSF challenge Molecular cell High 10678181
2001 In Schwann cells, Nf1 tumor suppressor function antagonizes the accumulation of cAMP and the expression of cyclin D1: ectopic expression of cyclin D1 using an inducible retroviral vector bypasses the G1 phase requirement for cAMP in Schwann cell proliferation, and loss of Nf1 increases cAMP and cyclin D1 levels, placing cyclin D1 as a downstream effector of Nf1-dependent growth control. Inducible retroviral expression of cyclin D1 in Schwann cells, cAMP measurement, cyclin D1 immunoblot, BrdU proliferation assay, Nf1-/- vs. wild-type Schwann cell comparison The Journal of neuroscience High 11160381
2002 Loss of NF1 specifically in the Schwann cell lineage (using cre/lox conditional allele driven by Schwann cell-specific Krox20/Egr2-Cre) is sufficient to generate neurofibromas; however, complete tumorigenesis also requires NF1 heterozygosity in the surrounding non-neoplastic microenvironment. Conditional Schwann cell-specific Nf1 knockout mouse (cre/lox), tumor histology, genetic epistasis with germline Nf1+/- background Science High 11988578
2006 CTCF mediates interchromosomal colocalization between the Igf2/H19 imprinting control region on chromosome 7 and the Wsb1/Nf1 locus on chromosome 11; deletion of the maternal ICR or omission of CTCF abrogates this association and alters Wsb1/Nf1 gene expression, establishing CTCF-dependent long-range transcriptional regulation of NF1. Modified chromosome conformation capture (3C), fluorescence in situ hybridization (FISH), CTCF knockdown, ICR deletion mouse model, RT-PCR of Wsb1/Nf1 expression Science Medium 16614224
2008 Nf1 heterozygosity in bone marrow-derived cells (specifically mast cells) in the tumor microenvironment is sufficient to allow neurofibroma progression when combined with Schwann cell Nf1 deficiency; genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression, identifying mast cells and c-kit signaling as critical mediators. Bone marrow transplantation between Nf1 genotypes, conditional Schwann cell Nf1 KO (DhhCre), c-kit genetic intercross, imatinib pharmacological inhibition, tumor histology and quantification Cell High 18984156
2008 Ras/Raf/ERK signaling drives de-differentiation of myelinating Schwann cells, a process relevant to NF1-associated tumor formation; Schwann cells lacking Nf1 show elevated Ras-ERK activity that promotes de-differentiation. Conditional NF1 knockout Schwann cells, Ras/ERK pathway assays, Schwann cell de-differentiation markers Cell cycle Low 15467460
2009 Skin-derived precursor (SKP) stem/progenitor cells residing in the dermis serve as the cell of origin for dermal neurofibromas upon loss of Nf1; non-neoplastic cells in the tumor microenvironment provide additional signals essential for neurofibromagenesis. Conditional Nf1 loss in SKPs (P0-Cre), tumor histology, lineage tracing, co-culture/transplantation experiments Cell stem cell Medium 19427294
2008 Nf1 loss of function amplifies an EGFR-dependent peripheral nerve progenitor pool in embryonic dorsal root ganglia; these Nf1-null progenitors are hypersensitive to growth factors, confer tumorigenesis in vivo, and human NF1 neurofibromas contain EGFR+/P75+ cells that form spheres and give rise to neurofibroma-like lesions in nude mice. In vitro sphere-formation assay, genetic (DhhCre;Nf1fl/fl) and pharmacologic (EGFR inhibition) tools, prospective FACS isolation of human EGFR+/P75+ cells, xenograft assay in nude mice Cell stem cell High 19041782
2010 NF1 null states in adult AML are associated with increased Ras-bound GTP; shRNA-mediated NF1 suppression in primary AML blasts with wild-type NF1 facilitates colony formation; NF1-null AML blasts show selective sensitivity to rapamycin-induced apoptosis, identifying mTOR as a survival dependency in NF1-null AML. SNP array, NF1 sequencing, Ras-GTP pulldown assay, shRNA knockdown, colony formation in methylcellulose, rapamycin treatment of primary blasts and CD34+/CD38- cells Clinical cancer research Medium 20505189
2010 In Nf1+/- mice, disruption of Ras regulation of inhibitory (GABAergic) neuronal networks is critical to the etiology of cognitive deficits; Nf1 haploinsufficiency increases GABA neurotransmitter pathway activity and MAPK signaling in neurons, and these phenotypes are rescued by pharmacological or genetic reduction of MAPK pathway activity. Nf1+/- mouse behavioral assays, electrophysiology, MAPK pathway inhibitors (lovastatin), genetic epistasis Annual review of neuroscience Low 20345245
2010 Nf1-/- Schwann cell-conditioned medium promotes increased degranulation of Nf1+/- mast cells compared with wild-type mast cells via secretion of Kit ligand (SCF); this effect is mediated by hyperactivation of the p21Ras-PI3K pathway, as demonstrated by genetic intercross and pharmacological inhibition. Schwann cell conditioned medium treatment of mast cells, degranulation assay, genetic Nf1/PI3K intercrosses, pharmacological PI3K inhibition, in vitro and in vivo measurements The American journal of pathology Medium 21037083
2011 Perinatal or adult induction of Nf1 loss in the Schwann cell lineage using tamoxifen-inducible PlpCre each cause neurofibroma formation; perinatal loss yields small neurofibromas late in life while adult loss causes large neurofibromas with earlier onset; EGFP reporter identifies that Nf1 loss in S100β+ myelinating and p75+ peripheral nerve Schwann cells but not GFAP+ non-myelinating Schwann cells contributes to tumors. A non-cell-autonomous effect of Nf1-deleted microenvironment on lympho-hematopoietic expansion was also identified. Tamoxifen-inducible PlpCre;Nf1fl/fl conditional knockout, conditional EGFP reporter lineage tracing, histological analysis, tumor timing/size quantification Cancer research Medium 21551249
2012 NF1 mutations cooperate with BRAF mutations in melanomagenesis by preventing oncogene-induced senescence (OIS); Nf1 mutations suppress Braf-induced senescence in a genetically engineered mouse model and function by deregulating both PI3K and ERK pathways; NF1 ablation decreases sensitivity of melanoma cell lines to BRAF inhibitors. Genetically engineered mouse model (BRAF+Nf1 mutations), senescence assays (SA-β-gal), proliferation assays, PI3K/ERK pathway biochemistry, BRAF inhibitor sensitivity assays in cell lines Cancer discovery High 23171796
2013 Nf1 deficiency in muscle results in neonatal lethality in muscle-specific knockouts; the limb-specific Nf1Prx1-/- conditional knockout shows 10-fold increased muscle triglyceride content, increased activities of oxidative metabolism enzymes, elevated fatty acid synthase and leptin expression, and decreased fatty acid transporters, establishing NF1 as essential for normal muscle energy metabolism. Conditional muscle-specific Nf1 knockout mice (Nf1muscle-/- and Nf1Prx1-/-), electron microscopy, Oil Red O staining, enzyme activity assays, Western blot Human molecular genetics Medium 24163128
2013 Ras-Erk signaling in neurofibromin-deficient macrophages is the aberrant pathway responsible for enhanced neointima formation in NF1: Nf1+/- macrophages show enhanced Erk signaling in vitro; in vivo Nf1+/- mice show increased intimal proliferation after carotid artery injury; MEK inhibitor PD0325901 reduces Nf1+/- neointima formation to wild-type levels without affecting PI3K signaling. Carotid artery injury model in Nf1+/- mice, ERK and PI3K phosphorylation assays, macrophage migration assays, PD0325901 pharmacological inhibition, morphometric neointima analysis The American journal of pathology Medium 24211110
2014 Neurofibromin regulation of cAMP in neurons requires RAS activation followed by atypical PKC-zeta activation, which drives GRK2-mediated Gαs inactivation; this was established using iPSC-derived NF1 patient neural progenitors and Nf1 genetically engineered mice, demonstrating that MEK/AKT pathways are not involved in the RAS→cAMP connection in neurons. iPSC-derived neural progenitors from NF1 patients, Nf1 genetically engineered mice, cAMP measurement, PKC-zeta inhibition, GRK2 knockdown, MEK/AKT inhibitors Human molecular genetics High 25070947
2014 Reduced NF1/neurofibromin expression impairs RAS-ERK signal attenuation downstream of mutant EGFR; erlotinib fails to fully inhibit RAS-ERK signaling when neurofibromin levels are reduced; MEK inhibitor treatment restores erlotinib sensitivity in neurofibromin-deficient lung cancer cells. Genome-wide siRNA screen in human lung cancer cells, Western blot (neurofibromin, pERK), MEK inhibitor combination treatment, murine EGFR-driven lung adenocarcinoma model Cancer discovery Medium 24535670
2014 Nf1+/- mice show a selective social learning deficit associated with greater activation of the MAPK pathway in amygdala and frontal cortex neurons; Nf1+/- amygdala exhibits aberrant glutamate and GABA neurotransmission, deficits in LTP, and specific disruptions in ADAM22 and HSP70 protein expression; all amygdala disruptions and social behavior deficits are rescued by deletion of Pak1 or pharmacological Pak1 blockade in the amygdala. Nf1+/- mouse behavioral testing, amygdala LTP electrophysiology, MAPK pathway Western blots, Pak1 genetic intercross, stereotaxic pharmacological injection of Pak1 inhibitors Nature neuroscience High 25242307
2014 MAF is an NF1-regulated transcription factor downstream of RAS/MAPK/AP-1 signaling; MAF re-expression promotes glial differentiation markers and affects MPNST cell death and growth; chronically elevated MAF enhances MPNST tumor growth in vivo through mTOR pathway activation via DEPTOR regulation; RAD001 blocks MAF-mediated tumor growth, establishing a RAS-MAPK→MAF→mTOR crosstalk mechanism. Transcriptome analysis, RT-PCR/Western blot validation, MAF overexpression in MPNST cell lines (inducible), in vivo tumor xenografts, RAD001 treatment, DEPTOR expression analysis Oncogene Medium 24509877
2016 Different NF1 germline mutations (R681X vs. G848R) result in different levels of neurofibromin expression and different optic glioma phenotypes; R681X mutation causes optic glioma formation with increased microglia infiltration and JNK/Ccl5/AKT activation in the microenvironment, while G848R does not; primary astrocytes with R681X show increased basal proliferation comparable to neo-CKO astrocytes, establishing germline mutation type as a cell-autonomous and stromal determinant of glioma development. Genetically engineered mice with patient-derived Nf1 mutations (R681X and G848R conditional KO), optic nerve volumetry/GFAP/BrdU immunostaining, retinal ganglion cell death assay, microglia quantification, phosphoprotein Western blots, primary astrocyte cultures Human molecular genetics High 26908603
2017 Nf1 deficiency in mature oligodendrocytes causes progressive myelin decompaction and behavioral abnormalities mediated by aberrant Notch activation; blocking Notch, upstream MAPK, or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants; gamma secretase inhibition rescues aberrant behavior; active Notch is increased in NF1 patient white matter, establishing Notch as a downstream effector of neurofibromin in oligodendrocyte myelin maintenance. Oligodendrocyte-specific conditional Nf1 knockout mice, myelin ultrastructure analysis, behavioral testing, Notch pathway inhibition (gamma secretase inhibitor), MEK inhibitor, NOS inhibitor, patient white matter immunostaining Cell reports High 28423318
2017 NF1 deficiency in fracture calluses leads to elevated β-catenin protein and activation of β-catenin-mediated signaling, resulting in delayed and fibrous fracture repair; pharmacological inhibition of β-catenin signaling with Nefopam rescues osteoblastic colony formation, bone content, and cartilage in Nf1-/- fracture calluses. Nf1-/- conditional mouse fracture model, β-catenin/Axin2 immunostaining and Western blot in patient and mouse tissue, bone marrow stromal cell osteoblast colony assay, histomorphometry of fracture callus, Nefopam pharmacological treatment Bone Medium 28254468
2018 Neurofibromin interacts with CRMP2 and uncouples CRMP2 from syntaxin 1A; loss of neurofibromin (NF1) frees CRMP2 to interact with both syntaxin 1A and CaV2.2, increasing CGRP release and causing pain hypersensitivity; CRISPR/Cas9 editing of Nf1 dysregulates NaV1.7 and CaV2.2, and the CRMP2-derived peptide CNRP1 targeting the CRMP2-neurofibromin interface reverses these ion channel dysregulations and thermal hyperalgesia. Co-immunoprecipitation (CRMP2/neurofibromin/syntaxin 1A/CaV2.2), CRISPR/Cas9 Nf1 editing in rats, neurotransmitter (CGRP) release assay, electrophysiology (NaV1.7, CaV2.2), thermal hyperalgesia behavioral assay, CNRP1 peptide rescue Neuroscience High 29655575
2018 Nf1 heterozygosity in the microenvironment accelerates formation of benign tumors but impairs malignant transformation, as shown in two orthogonal mouse models; an Nf1+/- microenvironment is tumor-promoting for benign lesions but antagonistic for progression to malignancy, reconciling the roles of NF1 in NF1-syndrome and sporadic cancers. Two independent mouse tumor models (NF1-related and non-NF1-related), conditional genetics, tumor incidence and progression analysis, human tumor data analysis Nature communications Medium 30479396
2019 Full-length neurofibromin forms a high-affinity dimer in vitro and in human cells; biophysical analyses (SEC-MALS, SAXS, SANS, analytical ultracentrifugation) and negative-stain EM reveal the overall dimer architecture; mixing N- and C-terminal protein domains reconstitutes dimer-like structures capable of GTPase activation in vitro; co-expression of the two domains in human cells recapitulates full-length neurofibromin activity. SEC-MALS, small-angle X-ray and neutron scattering, analytical ultracentrifugation, negative-stain EM, in vitro GTPase activation assay, co-IP in human cells, reconstitution from N- and C-terminal fragments The Journal of biological chemistry High 31836666
2021 Germline Nf1 mutation in retinal neurons causes aberrantly increased shedding of neuroligin-3 (NLGN3) within the optic nerve in response to retinal neuronal activity; NLGN3 shedding is required for Nf1-driven optic glioma initiation and progression; light deprivation prevents optic glioma formation; genetic Nlgn3 loss or pharmacological NLGN3 shedding inhibition blocks optic glioma formation, establishing neuronal activity–driven NLGN3 shedding as an obligate mechanism downstream of Nf1 mutation. Authenticated Nf1 mouse OPG model, light deprivation experiment, NLGN3 ELISA in optic nerve, Nlgn3 genetic KO rescue, pharmacological ADAM10 inhibitor (NLGN3 shedding inhibition), tumor volume MRI quantification Nature High 34040258
2023 Patient variants in NF1 codons 844–848 cause protein instability and exert a dominant-negative effect by destabilizing wild-type neurofibromin through the dimerization interface; cryo-EM structure of neurofibromin was used to predict additional patient variants with similar dominant-negative mechanism, validated experimentally, providing a structural basis for genotype-phenotype correlations. Cryo-EM structure determination, patient variant protein expression and stability assays, co-immunoprecipitation to demonstrate dimerization-dependent dominant-negative effect, computational prediction of destabilizing variants with experimental validation Proceedings of the National Academy of Sciences High 36689660

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science (New York, N.Y.) 475 11988578
2006 CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1. Science (New York, N.Y.) 378 16614224
2000 NF1 gene and neurofibromatosis 1. American journal of epidemiology 303 10625171
2008 Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell 274 18984156
2017 The NF1 somatic mutational landscape in sporadic human cancers. Human genomics 248 28637487
1996 Molecular genetics of neurofibromatosis type 1 (NF1). Journal of medical genetics 240 8825042
2012 Elucidating distinct roles for NF1 in melanomagenesis. Cancer discovery 199 23171796
1995 Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics 185 7774960
2021 NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature 182 34040258
2014 Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer discovery 173 24535670
2017 The NF1 gene in tumor syndromes and melanoma. Laboratory investigation; a journal of technical methods and pathology 162 28067895
2013 Neurofibromatosis type 1 (NF1): diagnosis and management. Handbook of clinical neurology 158 23931823
2014 The NF1 gene revisited - from bench to bedside. Oncotarget 144 25026295
2009 Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cell stem cell 140 19427294
2002 Plexiform neurofibromas in NF1: toward biologic-based therapy. Neurology 119 12041525
2000 Nf1 and Gmcsf interact in myeloid leukemogenesis. Molecular cell 118 10678181
2012 Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma. Human molecular genetics 115 22962301
2014 Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nature neuroscience 110 25242307
2017 NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics. Molecular oncology 104 28267273
2009 Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. The Journal of pathology 100 19142971
1997 Do NF1 gene deletions result in a characteristic phenotype? American journal of medical genetics 100 9375928
2002 Genetics of neurofibromatosis 1 and the NF1 gene. Journal of child neurology 99 12403554
2008 How does the Schwann cell lineage form tumors in NF1? Glia 97 18803326
2008 Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs). Human mutation 93 17960768
2001 Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1. The Journal of neuroscience : the official journal of the Society for Neuroscience 93 11160381
2015 NF1 Mutations Are Common in Desmoplastic Melanoma. The American journal of surgical pathology 90 26076063
2006 Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Human mutation 87 16941471
2016 Immortalization of human normal and NF1 neurofibroma Schwann cells. Laboratory investigation; a journal of technical methods and pathology 86 27617404
2010 Molecular and cellular mechanisms of learning disabilities: a focus on NF1. Annual review of neuroscience 86 20345245
1997 Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. Human genetics 83 9003501
2011 A highly sensitive genetic protocol to detect NF1 mutations. The Journal of molecular diagnostics : JMD 82 21354044
2012 Neoplasms associated with germline and somatic NF1 gene mutations. The oncologist 80 22240541
2011 The NF1 gene contains hotspots for L1 endonuclease-dependent de novo insertion. PLoS genetics 80 22125493
1995 Ras signaling and NF1. Current opinion in genetics & development 76 7749326
1995 Expression of the neurofibromatosis 1 (NF1) isoforms in developing and adult rat tissues. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 76 7794799
2014 Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation. Human molecular genetics 74 25070947
1999 Allelic loss of the NF1 gene in NF1-associated plexiform neurofibromas. Cancer genetics and cytogenetics 73 10459349
2018 NF1 mutations in conjunctival melanoma. British journal of cancer 72 29559732
1998 Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1. Journal of medical genetics 72 9643287
1994 Molecular basis of neurofibromatosis type 1 (NF1): mutation analysis and polymorphisms in the NF1 gene. Human mutation 71 7981724
2016 Clinical and Molecular Characteristics of NF1-Mutant Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 69 26861459
2016 NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1. Human molecular genetics 67 26908603
2016 Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only. EBioMedicine 65 27322474
2010 NF1 inactivation in adult acute myelogenous leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 62 20505189
2011 Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. Cancer research 57 21551249
2007 Recent insights into bone development, homeostasis, and repair in type 1 neurofibromatosis (NF1). Bone 57 18248783
2021 Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants. Human genetics 56 34928431
2018 NF1 deficiency correlates with estrogen receptor signaling and diminished survival in breast cancer. NPJ breast cancer 54 30182054
2016 Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression. BMC cancer 54 26925841
2009 The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics 51 19221814
2008 RAS signaling in colorectal carcinomas through alteration of RAS, RAF, NF1, and/or RASSF1A. Neoplasia (New York, N.Y.) 51 18592002
2006 Nf1 haploinsufficiency augments angiogenesis. Oncogene 47 16288202
2018 NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation. Nature communications 46 30479396
2004 Ras/Raf/ERK signalling and NF1. Cell cycle (Georgetown, Tex.) 46 15467460
2008 The role of steroid hormones in the NF1 phenotype: focus on pregnancy. American journal of medical genetics. Part A 43 18481270
1997 RNA processing and clinical variability in neurofibromatosis type I (NF1). Human molecular genetics 42 9300663
2019 Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. Journal of human genetics 41 31776437
2013 NF1 is a critical regulator of muscle development and metabolism. Human molecular genetics 41 24163128
1992 NF1-related locus on chromosome 15. Genomics 41 1505963
2017 Oligodendrocyte Nf1 Controls Aberrant Notch Activation and Regulates Myelin Structure and Behavior. Cell reports 40 28423318
2008 Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential. Cell stem cell 40 19041782
2019 Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer. The Journal of biological chemistry 39 31836666
2014 Neurofibromatosis type 1 (NF1) and associated tumors. Klinische Padiatrie 38 25062113
2016 GABA deficiency in NF1: A multimodal [11C]-flumazenil and spectroscopy study. Neurology 37 27473134
2016 Neurofibromatosis type 1 (NF1) gene: Beyond café au lait spots and dermal neurofibromas. Experimental dermatology 36 27622733
1989 Progress towards identifying the neurofibromatosis (NF1) gene. Trends in genetics : TIG 36 2506682
2020 Can the Cognitive Phenotype in Neurofibromatosis Type 1 (NF1) Be Explained by Neuroimaging? A Review. Frontiers in neurology 34 31993017
2014 MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1. Oncogene 33 24509877
2009 Neurofibroma development in NF1--insights into tumour initiation. Trends in cell biology 33 19615906
2019 After Nf1 loss in Schwann cells, inflammation drives neurofibroma formation. Neuro-oncology advances 32 32642730
2003 NF1 gene analysis based on DHPLC. Human mutation 32 12552569
2019 Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. Gene therapy 31 31127187
2010 Nf1-/- Schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phosphatidylinositol 3-kinase. The American journal of pathology 31 21037083
1999 Germline mutations in NF1 patients with malignancies. Genes, chromosomes & cancer 31 10534774
1993 Differential regulation of cellular activities by GTPase-activating protein and NF1. Molecular and cellular biology 31 8455625
2021 Severe Phenotype in Patients with Large Deletions of NF1. Cancers 30 34199217
2018 CRMP2-Neurofibromin Interface Drives NF1-related Pain. Neuroscience 30 29655575
2015 Clinicopathologic implications of NF1 gene alterations in diffuse gliomas. Human pathology 30 26190195
2021 Classification of NF1 microdeletions and its importance for establishing genotype/phenotype correlations in patients with NF1 microdeletions. Human genetics 29 34535841
2009 Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1. Clinical genetics 29 19845691
2004 Genomic organization and evolution of the NF1 microdeletion region. Genomics 29 15233998
2019 The Arg1038Gly missense variant in the NF1 gene causes a mild phenotype without neurofibromas. Molecular genetics & genomic medicine 28 30843352
2020 Advancement in research and therapy of NF1 mutant malignant tumors. Cancer cell international 26 33061844
2018 Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy. The Journal of clinical investigation 26 30226831
2013 Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation. The American journal of pathology 26 24211110
1996 Increased expression of the neurofibromatosis 1 (NF1) gene product, neurofibromin, in astrocytes in response to cerebral ischemia. Journal of neuroscience research 26 8820972
2011 The probable cell of origin of NF1- and PDGF-driven glioblastomas. PloS one 25 21931722
2023 Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization. Proceedings of the National Academy of Sciences of the United States of America 24 36689660
2023 NF1 alterations in cancers: therapeutic implications in precision medicine. Expert opinion on investigational drugs 24 37747491
2020 Clinical characterization of children and adolescents with NF1 microdeletions. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 24 32533297
2021 Non-Oncological Neuroradiological Manifestations in NF1 and Their Clinical Implications. Cancers 23 33921292
2017 Human stem cell modeling in neurofibromatosis type 1 (NF1). Experimental neurology 23 28392281
2015 Decoding NF1 Intragenic Copy-Number Variations. American journal of human genetics 23 26189818
1995 Expression of the neurofibromatosis type 1 (NF1) gene during mouse embryonic development. Progress in brain research 22 7568895
2021 Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq. NPJ genomic medicine 21 34782607
2018 Neurofibromin (NF1) genetic variant structure-function analyses using a full-length mouse cDNA. Human mutation 21 29522274
2006 NF1 mutation rather than individual genetic variability is the main determinant of the NF1-transcriptional profile of mutations affecting splicing. Human mutation 21 16937374
2017 Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair. Bone 20 28254468
1996 NF1 mRNA isoform expression in PC12 cells: modulation by extrinsic factors. Experimental cell research 20 8892969
2002 NF1 mutations and molecular testing. Journal of child neurology 19 12403553

Missed literature

Know a paper Affinage missed for NF1? Flag it for the maintainers and the community.

No submissions yet.