Affinage

NRAS

GTPase NRas · UniProt P01111

Round 2 corrected
Length
189 aa
Mass
21.2 kDa
Annotated
2026-04-29
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRAS encodes a membrane-anchored small GTPase that cycles between GDP-bound (inactive) and GTP-bound (active) conformations to transduce mitogenic, differentiation, and survival signals through effectors including C-RAF/MAPK, PI3Kγ/AKT, and JAK2/IL-8 pathways (PMID:20818433, PMID:11136978, PMID:26166574). Activation is driven by Sos1-mediated nucleotide exchange (PMID:8493579), while intrinsic GTPase activity is accelerated >200-fold by cytoplasmic GAP proteins — a stimulation abolished by oncogenic codon-12, -13, or -61 mutations that lock N-Ras in the GTP-bound state (PMID:2821624, PMID:6616621). Membrane targeting requires C-terminal farnesylation of Cys186 followed by palmitoylation of upstream cysteines, establishing a constitutive deacylation/reacylation cycle that dynamically partitions N-Ras between the Golgi apparatus and the plasma membrane; both lipid modifications are independently essential for leukemogenic activity (PMID:15705808, PMID:20200357). Beyond its oncogenic role, wild-type N-Ras restrains proliferation and functions as a tumor suppressor in thymocytes (PMID:12154063), operates in an Rb-dependent differentiation pathway in skeletal muscle (PMID:12861012), and drives cellular senescence and senescence-associated secretory phenotype in cholangiocytes (PMID:24390753).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1983 High

    Identification of N-ras as a transforming oncogene activated by a single codon-61 point mutation established that discrete mutations in a conserved GTPase convert it from proto-oncogene to oncogene, framing the central question of how nucleotide cycling is disrupted.

    Evidence Molecular cloning, DNA sequencing, and NIH3T3 focus assay of N-ras from human tumor DNA

    PMID:6595642 PMID:6616621

    Open questions at the time
    • Biochemical mechanism by which codon-61 mutations alter GTPase activity was unknown
    • Effector pathways downstream of activated N-Ras were unidentified
  2. 1987 High

    Demonstration that a cytoplasmic GAP stimulates N-Ras GTPase activity >200-fold and that oncogenic mutations render N-Ras refractory to GAP provided the biochemical explanation for why mutant N-Ras is constitutively GTP-loaded.

    Evidence In vitro GTPase assay with purified wild-type and mutant N-Ras proteins plus cytoplasmic GAP fraction; Xenopus oocyte maturation readout

    PMID:2821624

    Open questions at the time
    • Identity and structure of the GAP protein (later NF1) were not yet known
    • No structural explanation for why mutant Ras evades GAP stimulation
  3. 1987 High

    Reversion analysis in HT1080 cells showed that the activated N-ras allele is continuously required to maintain the transformed phenotype in a dosage-dependent manner, establishing that N-Ras is not merely an initiating event but a sustained driver.

    Evidence Isolation of revertants with reduced mutant N-ras p21, immunoprecipitation, retransfection

    PMID:3315232

    Open questions at the time
    • Downstream effectors mediating N-Ras-dependent transformation were unidentified
    • Whether oncogene addiction applies in vivo was untested
  4. 1989 High

    Systematic mutagenesis of the CAAX motif revealed that farnesylation of Cys186 is essential for membrane association and biological activity, while palmitoylation of upstream cysteines enhances membrane avidity and transforming potency, defining the dual-lipid modification requirement for N-Ras function.

    Evidence Cysteine mutagenesis, biosynthetic labeling, membrane fractionation, and transformation assays

    PMID:2661017

    Open questions at the time
    • Enzymes catalyzing palmitoylation and depalmitoylation were unknown
    • Subcellular site of each modification was not determined
  5. 1993 High

    Identification of hSos1 as the GEF for Ras, linking receptor tyrosine kinase signaling to N-Ras activation via the GRB2–Sos1 complex, completed the upstream activation mechanism.

    Evidence In vitro nucleotide exchange assay, yeast complementation, co-immunoprecipitation of Sos1 with GRB2

    PMID:8493579

    Open questions at the time
    • Whether Sos1 shows isoform preference among Ras proteins was not addressed
    • Structural basis for Sos-catalyzed exchange was unresolved
  6. 1998 High

    The crystal structure of the Ras–Sos complex revealed that Sos displaces Switch I via an inserted α-helix and distorts Switch II, providing the atomic mechanism of nucleotide exchange applicable to N-Ras.

    Evidence X-ray crystallography of H-Ras–Sos at 2.8 Å resolution

    PMID:9690470

    Open questions at the time
    • No structure of N-Ras specifically with Sos
    • Membrane context not captured in crystal structure
  7. 1999 High

    Live-cell imaging showed that N-Ras transits through the Golgi en route to the plasma membrane and that a secondary signal beyond the CAAX motif is required for PM delivery, establishing the endomembrane trafficking itinerary of N-Ras.

    Evidence GFP-N-Ras live-cell imaging, brefeldin A treatment, CAAX mutant analysis in COS cells

    PMID:10412982

    Open questions at the time
    • Whether Golgi-resident N-Ras signals to effectors was unknown
    • Identity of the secondary PM-targeting signal was not determined
  8. 1999 High

    Bone marrow transplant experiments showed that mutant N-Ras induces myeloproliferative disease and MDS in vivo, validating its role as a leukemia driver and revealing that high apoptosis accompanies transformation, consistent with a requirement for secondary hits.

    Evidence Retroviral transduction of N-Ras(G12D) into bone marrow, transplantation into irradiated mice, histopathology and colony assays

    PMID:10068678

    Open questions at the time
    • Cooperating mutations required for full AML were not identified
    • Effector pathway responsible for the myeloproliferative phenotype was undefined
  9. 2000 High

    The crystal structure of Ras–PI3Kγ demonstrated that Ras engages both the RBD and catalytic domain of PI3Kγ via Switch I and II, establishing the structural basis for Ras-dependent PI3K activation as a second major effector arm alongside RAF.

    Evidence X-ray crystallography plus in vitro PI3Kγ activation assay with mutagenesis

    PMID:11136978

    Open questions at the time
    • Whether N-Ras and K-Ras engage PI3Kγ with different affinities was not tested
    • In vivo contribution of PI3K vs. RAF downstream of N-Ras was unresolved
  10. 2002 High

    N-ras knockout mice developed thymic lymphomas at elevated rates and wild-type N-Ras overexpression was protective, revealing an unexpected tumor-suppressor function of the proto-oncogene product that counterbalances its oncogenic gain-of-function mutations.

    Evidence N-ras−/− and transgenic overexpression mouse models, soft-agar assays

    PMID:12154063

    Open questions at the time
    • Mechanism of tumor suppression (effector pathway, apoptosis vs. senescence) was not defined
    • Whether this function is tissue-restricted was unclear
  11. 2003 High

    Genetic epistasis in Rb−/−;N-ras−/− double-knockout embryos demonstrated that N-Ras and Rb function in a common skeletal muscle differentiation pathway, and that N-Ras deletion rescues Rb-null differentiation defects without correcting proliferation, separating the differentiation and proliferation arms of Rb signaling.

    Evidence Double-knockout mouse embryo histology, immunohistochemistry, MyoD transcriptional assays

    PMID:12861012

    Open questions at the time
    • Direct molecular link between N-Ras and Rb in differentiation was not identified
    • Whether this epistasis extends beyond skeletal muscle was untested
  12. 2005 High

    Discovery of a constitutive depalmitoylation/repalmitoylation cycle explained how N-Ras maintains dynamic equilibrium between Golgi and plasma membrane: depalmitoylation releases N-Ras to redistribute by default, and repalmitoylation traps it at the Golgi for vesicular transport to the PM.

    Evidence FRAP, live imaging, 2-bromopalmitate treatment, dominant-negative DHHC PAT constructs

    PMID:15705808

    Open questions at the time
    • Specific PAT and thioesterase enzymes responsible were not identified
    • Whether oncogenic mutations alter the acylation cycle kinetics was unknown
  13. 2005 High

    Identification of let-7 miRNA as a negative regulator of RAS expression via 3′ UTR binding sites provided the first post-transcriptional regulatory layer controlling N-Ras abundance, with reduced let-7 in tumors correlating with RAS overexpression.

    Evidence 3′ UTR reporter assay, let-7 overexpression/Western blot, C. elegans genetic epistasis

    PMID:15766527

    Open questions at the time
    • Relative contribution of let-7 to N-Ras vs. K-Ras regulation was not quantified
    • In vivo therapeutic relevance of let-7 restoration was not tested
  14. 2008 High

    eNOS-derived NO was shown to selectively activate N-Ras (not K-Ras) at the Golgi of T cells via S-nitrosylation of Cys118, linking the previously identified Golgi-localized pool to a specific activation mechanism and functional outcome — TCR-dependent apoptosis.

    Evidence Ras-GTP biosensors in T cells expressing eNOS-GFP, S-nitrosylation assay, C118S mutagenesis, apoptosis assay

    PMID:18641128

    Open questions at the time
    • Whether S-nitrosylation of N-Ras occurs in non-immune cell types was unknown
    • Structural basis for isoform selectivity of Cys118 nitrosylation was not defined
  15. 2010 High

    In vivo demonstration that non-palmitoylatable NRAS mutants completely fail to induce leukemia, while farnesylation-deficient mutants also fail through a distinct mechanism, established that both lipid modifications are independently required for N-Ras oncogenic signaling in hematopoietic cells.

    Evidence Retroviral bone marrow transduction/transplantation with palmitoylation-deficient and farnesylation-deficient NRAS mutants

    PMID:20200357

    Open questions at the time
    • Downstream signaling differences between palmitoylation-deficient and farnesylation-deficient N-Ras were not characterized
    • Whether palmitoylation inhibition is therapeutically tractable was untested
  16. 2010 High

    Identification of activating N-RAS mutations as a mechanism of acquired resistance to BRAF inhibitors in melanoma, mediated by C-RAF-dependent MAPK reactivation, placed N-Ras at the center of therapeutic resistance and established the N-Ras–C-RAF axis as a clinically relevant signaling route.

    Evidence Resistant melanoma subline derivation, siRNA knockdown, N-RAS(Q61K) overexpression, patient biopsy validation

    PMID:20818433 PMID:21107323

    Open questions at the time
    • Whether combined MEK + BRAF inhibition fully overcomes N-RAS-driven resistance was not resolved
    • Contribution of PI3K signaling to resistance in N-RAS-mutant context was not addressed
  17. 2015 High

    Discovery that wild-type N-Ras directly binds and activates cytoplasmic JAK2 to induce IL-8 secretion in basal-like breast cancer — an isoform-specific function not shared by K-Ras — expanded the effector repertoire of N-Ras beyond canonical RAF and PI3K pathways.

    Evidence Co-immunoprecipitation of N-Ras with JAK2, IL-8 secretion assays, isoform-specific knockdown/overexpression, in vivo tumor formation

    PMID:26166574

    Open questions at the time
    • Structural basis for N-Ras isoform selectivity in JAK2 binding was not determined
    • Whether this mechanism operates in non-breast cancer contexts was unknown
  18. 2018 Medium

    Comparative crystallography revealed that K-Ras, N-Ras, and H-Ras G domains adopt isoform-specific conformational preferences in switch regions despite identical sequences at mutation hotspots, providing a structural rationale for isoform-selective effector coupling and cancer-type associations.

    Evidence Comparative X-ray crystallography of wild-type Ras isoform G domains

    PMID:29038336

    Open questions at the time
    • Functional validation that these conformational differences dictate isoform-specific effector selection was lacking
    • No structure of full-length lipidated N-Ras in a membrane context

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite detailed knowledge of N-Ras lipid modification, trafficking, and oncogenic signaling, no isoform-selective direct inhibitor of N-Ras exists; the specific PAT and thioesterase enzymes governing N-Ras palmitoylation cycling remain incompletely defined, and how N-Ras isoform-specific conformational dynamics translate into selective effector engagement in vivo is unresolved.
  • No direct small-molecule inhibitor of N-Ras GTPase
  • Identity and regulation of the specific DHHC palmitoyltransferase(s) and thioesterase(s) for N-Ras
  • Full-length membrane-bound N-Ras structure at atomic resolution

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0003924 GTPase activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005794 Golgi apparatus 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953854 Metabolism of RNA 2
Partners
CRAFGRB2JAK2PIK3CGRASA1SOS1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 The human N-ras gene was cloned and shown to have the same intron/exon structure as H-ras and K-ras; a single nucleotide change substituting lysine for glutamine at position 61 of the N-ras product converts it from a non-transforming proto-oncogene to a transforming oncogene, demonstrating that codon 61 is a critical activation site. Molecular cloning, DNA sequencing, NIH3T3 transfection/focus assay Cell High 6616621
1983 The human N-ras gene was mapped by in situ hybridization to chromosome 1, region 1cen–p21. In situ hybridization to metaphase chromosome preparations The EMBO journal High 6667677
1984 Three distinct activating point mutations were identified at codon 61 of N-ras in human tumor cell lines (fibrosarcoma HT1080, promyelocytic HL60, rhabdomyosarcoma RD301), affecting the first, second, or third nucleotide of the codon respectively, all resulting in amino acid substitutions and demonstrating dominant oncogenic character alongside a normal N-ras allele. Synthetic oligonucleotide hybridization, DNA sequencing Nucleic acids research High 6595642
1987 A cytoplasmic protein (later identified as GAP/NF1) stimulates GTP hydrolysis by normal N-ras p21 (Gly12) more than 200-fold in vitro but has no effect on oncogenic mutants (Asp12 or Val12), explaining how position-12 mutations lock N-ras in the active GTP-bound state by preventing GTPase-activating protein stimulation. Xenopus oocyte maturation assay (biological activity readout), in vitro GTPase assay with purified proteins, in vivo GTP/GDP binding analysis Science High 2821624
1987 The activated N-ras oncogene of HT1080 human fibrosarcoma cells directly maintains the transformed phenotype; revertants with reduced mutant N-ras p21 levels lost transformation, and sporadic tumors from revertants regained the transforming allele, demonstrating that N-ras oncogene dosage controls the transformed state. Revertant isolation, immunoprecipitation of N-ras p21, gene dosage analysis, retransfection of cloned ras oncogenes Cell High 3315232
1986 Activated N-ras transfected into PC12 rat pheochromocytoma cells suppressed proliferation and promoted neuronal differentiation (neurite outgrowth, cell division arrest), including in NGF-resistant variants, demonstrating that N-ras can drive differentiation rather than proliferation in a cell-context-dependent manner. Gene transfection, morphological assessment of neurite outgrowth, cell proliferation assays Journal of cellular physiology Medium 3760034
1988 Steroid-inducible oncogenic N-ras expression in C2 myoblasts reversibly inhibited myotube formation and induction of muscle creatine kinase and acetylcholine receptors in a dose-dependent manner, without affecting growth factor dependence or contact inhibition; however, N-ras induction in terminally differentiated myotubes failed to extinguish muscle-specific gene expression, placing N-ras action at an early step in the myogenic differentiation pathway. MMTV-LTR steroid-inducible N-ras transgene system in C2 myoblasts; dexamethasone dose–response; muscle-specific gene expression assays (MCK, AChR); conditioned media experiments The Journal of cell biology High 3133379
1989 All Ras proteins including N-Ras are polyisoprenylated (farnesylated) on the C-terminal cysteine (Cys186); palmitoylation occurs on additional upstream cysteine residues in the hypervariable domain rather than on Cys186; palmitoylation increases membrane avidity and enhances transforming activity, while polyisoprenylation is essential for membrane association and biological activity. Mutational analysis of CAAX motif cysteines, membrane association assays, transformation assays, biosynthetic labeling Cell High 2661017
1993 Human Sos1 (hSos1), a guanine nucleotide exchange factor closely related to Drosophila Sos, directly stimulates guanine nucleotide exchange on Ras proteins (including N-Ras) in vitro via its CDC25-related domain; hSos1 interacts with GRB2 through its C-terminal domain binding to GRB2 SH3 domains in vivo and in vitro, placing Sos1 as the direct activator of Ras downstream of receptor tyrosine kinases. CDC25 yeast complementation, in vitro guanine nucleotide exchange assay, mammalian overexpression, in vivo and in vitro co-immunoprecipitation with GRB2 Science High 8493579
1997 The farnesylated C-terminal peptide of N-ras is reversibly S-acylated (palmitoylated) in cultured mammalian fibroblasts; S-acylation occurs specifically on cysteine (not serine), suppresses membrane desorption/diffusion between bilayers, and is required for preferential plasma membrane localization; the plasma membrane targeting is unaffected by brefeldin A or reduced temperature, suggesting a 'kinetic trapping' mechanism at the plasma membrane rather than trafficking through the secretory pathway. Fluorescent lipid-modified peptide analogs, large unilamellar vesicle binding assays, fluorescence microscopy in CV-1 cells, brefeldin A and temperature inhibition experiments Biochemistry High 9335573
1998 Crystal structure of H-Ras complexed with the Sos GEF domain at 2.8 Å resolution revealed that Sos displaces the Switch I region of Ras by inserting an α-helix, opening the nucleotide-binding site, and disrupts magnesium/phosphate binding via Switch II distortion, defining the catalytic mechanism of Ras nucleotide exchange applicable to all Ras isoforms including N-Ras. X-ray crystallography at 2.8 Å resolution, structure-function analysis Nature High 9690470
1999 N-ras is transiently localized to the Golgi apparatus en route to the plasma membrane; GFP-tagged N-ras labeled motile peri-Golgi vesicles; prolonged brefeldin A treatment blocked plasma membrane expression; the CAAX motif alone targets N-ras to endomembranes where carboxylmethylation occurs, and a secondary targeting signal is required for final plasma membrane delivery. GFP fusion live-cell imaging, brefeldin A treatment, CAAX motif mutational analysis, carboxylmethylation assay Cell High 10412982
1999 Mutant N-ras expression in bone marrow-repopulated mice induced myeloproliferative disorders resembling CML or AML-M2 in ~60% of animals, as well as MDS-like disorders with myeloid impairment; a high level of apoptosis with thymic atrophy was also observed, consistent with a model where antiproliferative effects are a primary consequence of N-ras mutations and secondary events are needed for leukemia. Retroviral bone marrow transduction and transplantation mouse model, histopathology, CFU-S and colony assays, flow cytometry Blood High 10068678
1999 Mutated N-ras specifically upregulates Bcl-2 protein expression in human melanoma cells in vitro and in SCID mouse xenografts, protecting against apoptosis; neither Bcl-xL, Bax, nor Bak expression was altered, identifying Bcl-2 upregulation as the mechanistic basis of N-ras-mediated apoptosis resistance. N-ras overexpression in melanoma cell lines, Western blot for apoptosis-related proteins, SCID mouse xenograft model Melanoma research Medium 10504052
2000 Crystal structure of PI3Kγ in complex with H-Ras·GMPPNP revealed that Ras uses both Switch I and Switch II regions to bind the PI3Kγ RBD, and Ras also contacts the PI3Kγ catalytic domain directly; mutagenesis confirmed both switch regions are essential for binding and activation, establishing the structural basis for Ras-dependent PI3K activation relevant to all Ras isoforms including N-Ras. X-ray crystallography, in vitro PI3Kγ activation assay with H-Ras G12V, site-directed mutagenesis Cell High 11136978
2002 Wild-type N-ras acts as a tumor suppressor: N-ras-null mice develop thymic lymphomas at higher rates, whereas overexpression of wild-type N-ras protects against thymic lymphomagenesis; introduction of wild-type N-ras into N-ras-deficient tumor cells decreased growth in low serum and soft agar, demonstrating a growth-inhibitory role for the proto-oncogene product. N-ras knockout and transgenic mouse models, in vitro transformation assays (low-serum growth, soft-agar colony formation) Cancer research High 12154063
2003 Rb and N-ras function in a common pathway to control skeletal muscle differentiation: deletion of N-ras in Rb-null embryos rescued defects in skeletal muscle fiber density, myotube morphology, and MCK expression, and potentiated MyoD transcriptional activity, while proliferation and apoptosis defects remained; this genetic rescue demonstrates that N-ras and Rb operate in the same differentiation pathway but that Rb's control of differentiation is separable from its control of proliferation. Double-knockout mouse embryo analysis (Rb−/−; N-ras−/−), histology, immunohistochemistry, MyoD transcriptional activity assay in primary myoblasts Molecular and cellular biology High 12861012
2005 Let-7 miRNA family members negatively regulate RAS expression (including N-RAS) by binding multiple let-7 complementary sites (LCSs) in the 3′ UTR of human RAS genes; let-7 overexpression reduces RAS protein levels, and let-7 is lower in lung tumors that overexpress RAS protein. 3′ UTR reporter assays, let-7 overexpression, Western blot for RAS protein in tumor vs. normal tissue; C. elegans genetic epistasis (let-60/RAS) Cell High 15766527
2005 A constitutive de/reacylation (palmitoylation/depalmitoylation) cycle drives rapid exchange of N-ras and H-ras between the plasma membrane and the Golgi apparatus: depalmitoylation redistributes farnesylated N-ras to all membranes, repalmitoylation traps it at the Golgi, and vesicular transport then delivers it to the plasma membrane; this cycle maintains compartment-specific localization and enables Golgi-initiated Ras activation. Fluorescent N-ras fusion proteins (FRAP, live imaging), palmitoylation inhibitor 2-bromopalmitate, dominant-negative DHHC PAT constructs, quantitative membrane fractionation Science High 15705808
2005 Galectin-3 selectively binds activated K-Ras-GTP (not N-Ras-GTP); Gal-3 overexpression in breast cancer cells increased K-Ras-GTP while reducing N-Ras-GTP, demonstrating a molecular switch between N-Ras and K-Ras usage dependent on Gal-3 binding; only wild-type Gal-3 co-immunoprecipitated with K-Ras and altered signaling from AKT/Ral toward ERK. Co-immunoprecipitation, RAS activation (GTP pull-down) assays, Gal-3 point mutants, isoform-specific RBD pull-down Cancer research Medium 16103080
2006 Fully lipidated (farnesylated + hexadecylated) N-Ras protein partitions preferentially into liquid-disordered (ld) lipid domains rather than liquid-ordered (lo) or solid-ordered phases in model membranes; a large proportion also localizes at ld/lo phase boundaries, reducing line tension; this membrane domain preference is independent of nucleotide (GDP vs GTP) state. Two-photon fluorescence microscopy on giant unilamellar vesicles, tapping-mode AFM on supported bilayers, canonical raft lipid mixture (POPC/sphingomyelin/cholesterol) Journal of the American Chemical Society Medium 16390147
2006 Solid-state NMR of full-length membrane-associated lipidated N-Ras protein revealed that the C-terminal lipid anchor region is highly flexible with segmental fluctuations and axially symmetric overall motions on the membrane surface; the palmitoyl chain at Cys181 is highly mobile in the membrane. Solid-state 2H and 13C NMR, chemical-biological ligation of isotopically labeled lipidated heptapeptide to expressed N-terminal domain, order parameter and relaxation measurements Journal of the American Chemical Society High 17044712
2008 eNOS-derived NO selectively activates N-Ras (but not K-Ras) on the Golgi complex of T cells engaged with antigen-presenting cells; activation involves eNOS-dependent S-nitrosylation of N-Ras at Cys118; wild-type but not C118S N-Ras increased TCR-dependent apoptosis, demonstrating that S-nitrosylation of Cys118 is required for N-Ras activation at the Golgi and contributes to activation-induced T cell death. Fluorescent Ras probes (Ras-GTP biosensors) in T cells stably expressing eNOS-GFP or G2A mutant; S-nitrosylation assay; site-directed mutagenesis (C118S); apoptosis assay Proceedings of the National Academy of Sciences High 18641128
2009 N-Ras proteins bearing at least one farnesyl group partition preferentially into liquid-disordered lipid domains independent of lipid anchor type; farnesylated N-Ras shows diffusion to ld/lo phase boundaries and forms nanoclusters there via intermolecular interactions; the non-biological dual-hexadecyl N-Ras instead incorporates into the bulk ld phase without boundary preference; no significant difference in domain partitioning was detected between GDP- and GTP-loaded N-Ras. Time-lapse tapping-mode AFM on supported lipid bilayers, differently lipidated N-Ras protein variants Journal of the American Chemical Society Medium 19133719
2010 Palmitoylation is essential for leukemogenesis by oncogenic NRAS: non-palmitoylatable NRAS mutants failed to induce CMML/AML in a mouse bone marrow transplant model; farnesylation is also essential but through a distinct mechanism from palmitoylation deficiency; demonstrating that both post-translational lipid modifications are independently required for NRAS oncogenic activity. Retroviral bone marrow transduction/transplantation mouse model, palmitoylation-deficient and farnesylation-deficient NRAS mutants Blood High 20200357
2010 In NRAS-mutant melanoma cells, PLX4720 (BRAF inhibitor) rapidly induces hyperactivation of MEK-ERK1/2 signaling; C-RAF (not B-RAF) is the major RAF isoform responsible for this hyperactivation; PLX4720-induced MEK-ERK1/2 hyperactivation promotes resistance to apoptosis in N-RAS mutant melanoma cells but does not enhance cell cycle progression. PLX4720 treatment of N-RAS mutant melanoma cells, phospho-ERK1/2 Western blot, siRNA knockdown of RAF isoforms, apoptosis assays Oncogene High 20818433
2010 Acquired resistance to PLX4032 (BRAF inhibitor) in melanoma arises through mutually exclusive mechanisms: PDGFR-β upregulation (maintaining low activated RAS) or activating N-RAS mutations (causing MAPK reactivation upon PLX4032 treatment); knockdown of N-RAS reduced growth of the N-RAS-mutant resistant subset; overexpression of N-RAS(Q61K) conferred PLX4032 resistance to sensitive parental cells; MAPK reactivation predicted MEK inhibitor sensitivity. PLX4032-resistant melanoma subline derivation, siRNA knockdown, overexpression of N-RAS(Q61K), phospho-MAPK pathway analysis, patient biopsy validation Nature High 21107323
2010 miR-214 promotes myogenic differentiation in C2C12 myoblasts by down-regulating N-ras, facilitating cell cycle exit; blocking miR-214 maintained active cell cycling and inhibited differentiation; siRNA knockdown of N-Ras augmented the differentiation effect while forced N-Ras overexpression attenuated it, placing N-Ras downstream of miR-214 in the differentiation pathway. 2′-O-methylated miR-214 inhibitor, global gene expression profiling, siRNA knockdown and adenoviral overexpression of N-Ras, cell cycle analysis, muscle differentiation markers The Journal of biological chemistry High 20534588
2011 Pressure modulation combined with FTIR spectroscopy revealed distinct conformational substates of lipidated N-Ras; nucleotide-binding state (GDP vs GTP) and membrane binding both dramatically alter conformational dynamics and substate selection; a new membrane-induced conformational substate was identified, accompanied by structural reorientation of the G domain as shown by ATR-FTIR and IRRAS, demonstrating that the membrane acts as an allosteric regulator of N-Ras G-domain orientation. Pressure-perturbation FTIR spectroscopy, ATR-FTIR, IRRAS on membrane-associated lipidated N-Ras Proceedings of the National Academy of Sciences High 22203965
2013 N-Ras deficiency in fibroblasts resulted in higher basal PI3K/Akt and MEK/Erk activity, upregulated collagen synthesis, and diminished proliferation and migration; TGF-β1-induced proliferation and migration required PI3K/Akt but not Erk1/2; N-Ras modulates extracellular matrix synthesis and cell motility by negatively regulating Akt activation, indicating N-Ras normally restrains collagen production and regulates fibroblast behavior. N-ras−/− immortalized fibroblasts, Western blot for pathway activation, collagen/fibronectin expression, proliferation and migration assays, pharmacological PI3K/MEK inhibitors Biochimica et biophysica acta Medium 23871832
2014 miR-143 directly targets N-RAS 3′ UTR and suppresses N-RAS expression; overexpression of miR-143 decreased N-RAS protein, inhibited PI3K/AKT and MAPK/ERK signaling, reduced p65 nuclear accumulation, and attenuated glioma cell migration, invasion, tube formation, and tumor growth in vitro and in vivo. miR-143 overexpression, luciferase 3′ UTR reporter assay, Western blot, invasion/migration assays, xenograft mouse model Oncotarget Medium 24980823
2014 N-Ras activation via biliary constituents induces cholangiocyte senescence and senescence-associated secretory phenotype (SASP, including IL-6, IL-8, CCL2, PAI-1) in primary sclerosing cholangitis; pharmacological Ras inhibition abrogated experimentally induced senescence and SASP; senescent cholangiocytes could transmit senescence to bystander cells, placing N-Ras upstream of the senescence program in cholangiocytes. IFM, FISH (telomere length), in vitro cholangiocyte senescence induction, Ras inhibitor (farnesylthiosalicylic acid), co-culture bystander assay, patient liver biopsies Hepatology Medium 24390753
2015 Wild-type N-Ras, overexpressed in basal-like breast cancers, promotes tumor formation specifically by binding and activating cytoplasmic JAK2, leading to IL-8 secretion that acts on both cancer cells and stromal fibroblasts in an autocrine/paracrine manner; this activity is isoform-specific as K-Ras did not induce IL-8 via JAK2. N-RAS knockdown and overexpression in BLBC cells, co-immunoprecipitation of N-Ras with JAK2, IL-8 secretion assays, fibroblast co-culture, tumor formation assays in vivo Cell reports High 26166574
2015 L. major enhances CD40-induced N-Ras activation in macrophages via TLR2-dependent signaling; N-Ras silencing reduced L. major infection while K-Ras and H-Ras silencing enhanced it; cell-permeable peptides blocking the N-Ras–Sos interaction interface reduced L. major infection in BALB/c mice but not in CD40-deficient mice, demonstrating isoform-specific N-Ras function downstream of CD40 in Leishmania immune evasion. shRNA knockdown of individual Ras isoforms, TLR2 shRNA/antibody blockade, RAS activation assays, N-Ras–Sos interface peptide inhibitors in vivo (BALB/c mice), CD40 KO mice Journal of immunology Medium 25786685
2018 Structural comparisons of K-Ras, N-Ras, and H-Ras G domains revealed that each isoform and each oncogenic mutation has distinct conformational preferences in switch regions I and II and the allosteric lobe, despite 100% sequence identity in the mutation hotspot regions; these structural differences can account for isoform-specific coupling to effectors and cancer types. Comparative X-ray crystallography of wild-type Ras isoforms, structural analysis of switch region conformations Cold Spring Harbor perspectives in medicine Medium 29038336

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 RAS is regulated by the let-7 microRNA family. Cell 2895 15766527
2013 Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. The New England journal of medicine 1802 24024839
2010 Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 1752 21107323
2010 Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. The Lancet. Oncology 1728 20619739
1989 All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 1708 2661017
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2012 A comprehensive survey of Ras mutations in cancer. Cancer research 1612 22589270
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. The New England journal of medicine 1315 18450602
1987 A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science (New York, N.Y.) 1170 2821624
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2001 Nerve growth factor signaling, neuroprotection, and neural repair. Annual review of neuroscience 1029 11520933
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
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