Affinage

NRAS

GTPase NRas · UniProt P01111

Length
189 aa
Mass
21.2 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRAS encodes a small GTPase that cycles between GDP- and GTP-bound states and drives proliferation, differentiation, and immune signaling through Raf/MEK/ERK and PI3K/AKT outputs (PMID:6616621, PMID:16624289). Oncogenic activation arises from point mutations at codons 12, 13, or 61 that reduce intrinsic GTPase activity and lock the protein in its active state; reduced hydrolysis rather than altered nucleotide binding underlies transformation (PMID:6616621, PMID:3550423), and such mutations suppress differentiation programs such as myoblast fusion (PMID:3600660) while driving hematopoietic malignancy and melanoma, including acquired resistance to B-RAF inhibition through MAPK reactivation (PMID:21107323) and STAT3-dependent apoptosis evasion in colorectal tumors (PMID:23274911). Signaling competency depends on lipid-directed trafficking: N-Ras is farnesylated, or alternatively geranylgeranylated when farnesyltransferase is blocked (PMID:9162087), and is then S-palmitoylated by the Golgi-resident DHHC9·GCP16 complex to target it to the plasma membrane (PMID:16000296, PMID:9335573), where it preferentially partitions into liquid-disordered lipid domains (PMID:16390147) and adopts membrane-controlled signaling conformations (PMID:22203965). Palmitate is removed by ABHD17-family depalmitoylases to permit redistribution (PMID:26701913), while the VPS35 retromer binds farnesylated, non-palmitoylated N-Ras as a cytosolic chaperone governing trafficking and GTP loading (PMID:27502489). Activation occurs exclusively at the plasma membrane in a palmitoylation-dependent manner downstream of growth factor receptors, TCR engagement, and plasma-membrane Toll-like receptors (PMID:23758196, PMID:20713885, PMID:21757746). N-Ras is physiologically required for T-cell function, including CD8 thymocyte development, IL-2 production, and Th1/IFN-γ responses (PMID:12670913, PMID:21444916), and operates in a common differentiation pathway with pRb (PMID:12861012). Distinct from K-Ras and H-Ras, N-Ras has isoform-specific intrinsic hydrolysis kinetics set by allosteric structural features (PMID:28630043) and uniquely binds and activates cytoplasmic JAK2 to drive IL-8 secretion (PMID:26166574).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1983 High

    Established that a single point mutation is sufficient to convert N-ras into an oncogene, defining codon 61 (alongside codon 12) as an activation hotspot.

    Evidence Gene cloning, sequencing, and NIH 3T3 transformation assay

    PMID:6616621

    Open questions at the time
    • Did not define the biochemical defect caused by the mutation
    • No mechanism linking the mutant to downstream effectors
  2. 1985 High

    Confirmed across melanoma and rhabdomyosarcoma that codon 61 substitutions alone confer transforming activity, generalizing the activation mechanism beyond a single tumor type.

    Evidence Cloning, sequencing, and transfection/transformation assays in tumor-derived lines

    PMID:3158613 PMID:3887133

    Open questions at the time
    • Did not quantify how the mutation alters GTPase function
    • No downstream pathway readout
  3. 1987 High

    Pinned the molecular basis of oncogenicity to reduced GTP hydrolysis rather than altered nucleotide binding, and showed oncogenic N-Ras blocks differentiation independent of proliferation.

    Evidence Recombinant mutant proteins with in vitro GTPase/binding assays, microinjection, and differentiation assays in C2 myoblasts

    PMID:3550423 PMID:3600660

    Open questions at the time
    • Did not identify the downstream effectors mediating differentiation block
    • No structural explanation for the GTPase defect
  4. 1997 High

    Defined how N-Ras achieves membrane association, showing alternative geranylgeranylation under FTI treatment and palmitoylation-dependent kinetic trapping at the plasma membrane.

    Evidence Cell-based prenylation/fractionation under FTI, and lipidated peptide reconstitution with fluorescence microscopy and pharmacological perturbation

    PMID:9162087 PMID:9335573

    Open questions at the time
    • Palmitoyltransferase enzyme not yet identified
    • Did not address how depalmitoylation reverses targeting
  5. 1997 Medium

    Identified transcriptional interference from the upstream unr gene as a regulator of N-ras mRNA levels.

    Evidence Homologous recombination deletion of the unr promoter in mice with RNase protection of N-ras mRNA

    PMID:9450542

    Open questions at the time
    • Modest effect size (20-65%)
    • Physiological consequence of altered N-ras levels not tested
  6. 1998 Medium

    Demonstrated isoform-selective upstream and downstream coupling, with the hypervariable domain dictating GEF specificity and N-Ras contributing to MAPK output even in H-ras-transformed cells.

    Evidence In vivo GEF selectivity assays, co-IP with Raf-1, and antisense knockdown of c-N-Ras

    PMID:9430727 PMID:9525741

    Open questions at the time
    • Single-lab co-IP without structural validation
    • Mechanism of differential GEF engagement at residue level not resolved
  7. 1999 Medium

    Showed oncogenic N-Ras remodels the Golgi and cytoskeleton and enhances secretory transport, linking it to organelle physiology beyond canonical signaling.

    Evidence Conditional N-Ras(K61) expression in NRK cells with EM, stereology, transport assays, and PLA2 inhibition

    PMID:9914160

    Open questions at the time
    • Effector pathway connecting N-Ras to Golgi collapse unclear
    • PLA2 inhibitor effect only partial
  8. 2001 Medium

    Distinguished N-Ras from K-Ras by negative regulation, showing calmodulin binds and modulates K-Ras but not N-Ras.

    Evidence Calmodulin affinity chromatography and Ras activation assays across isoforms

    PMID:11585916

    Open questions at the time
    • Negative result for N-Ras; does not define an N-Ras-specific regulator
    • Single-lab biochemistry
  9. 2003 High

    Defined physiological roles of N-ras in tumor suppression, T-cell immunity, and Rb-dependent differentiation through genetic loss-of-function in mice.

    Evidence N-ras knockout, transgenic overexpression, and Rb;N-ras double-knockout mouse models with phenotypic and molecular readouts

    PMID:12154063 PMID:12670913 PMID:12861012

    Open questions at the time
    • Mechanistic link between N-Ras and the Rb/MyoD axis not biochemically resolved
    • Compensation by other Ras isoforms not fully excluded
  10. 2005 High

    Identified the enzyme responsible for N-Ras palmitoylation, establishing DHHC9·GCP16 as a Golgi-localized palmitoyltransferase with substrate specificity for N-Ras and H-Ras.

    Evidence Reconstituted in vitro palmitoyltransferase assay with substrate specificity testing, co-IP, and Golgi localization microscopy

    PMID:16000296

    Open questions at the time
    • Did not define how depalmitoylation is achieved
    • In vivo requirement for N-Ras signaling not tested in this study
  11. 2006 Medium

    Extended N-Ras roles to TGF-β-driven fibroblast biology and revealed gelsolin as a physical partner mediating an antiapoptotic function modulated by K-Ras status.

    Evidence H-ras/N-ras double-knockout fibroblasts with pathway dissection, and co-IP of endogenous N-Ras with gelsolin in isogenic K-RAS lines

    PMID:16624289 PMID:17130841

    Open questions at the time
    • Single-lab co-IP for the gelsolin interaction
    • Direct contribution of gelsolin binding to apoptosis resistance not isolated
  12. 2006 High

    Provided biophysical basis for membrane preference, showing lipidated N-Ras favors liquid-disordered domains and phase boundaries.

    Evidence Two-photon fluorescence microscopy and AFM on giant unilamellar vesicles with fully lipidated N-Ras

    PMID:16390147

    Open questions at the time
    • Reconstituted model system; in-cell phase behavior not directly shown
    • Functional consequence of domain preference for signaling not addressed here
  13. 2008 Medium

    Identified galectin-3 as an isoform-selective negative regulator of N-Ras/H-Ras activation by inhibiting RasGRP4-mediated GTP loading.

    Evidence Co-IP, RasGRP4 GEF activity assays, and Gal-3 shRNA knockdown with Ras activation readouts

    PMID:18413234

    Open questions at the time
    • Single-lab mechanism
    • Structural basis of selective inhibition not resolved
  14. 2009 Medium

    Linked Rb loss to N-Ras activation via E2F-driven prenyltransferase upregulation, coupling N-Ras hyperactivity to senescence and DNA damage response.

    Evidence Rb-heterozygous mouse model with E2F target analysis, N-Ras activity assays, and senescence readouts

    PMID:19345325

    Open questions at the time
    • Causal sufficiency of prenylation increase not fully isolated
    • Single-model system
  15. 2010 High

    Demonstrated activation occurs exclusively at the plasma membrane in a palmitoylation-dependent manner downstream of TCR signaling.

    Evidence Live-cell Ras-GTP imaging with affinity probes and palmitoylation-deficient mutants in Jurkat and primary T cells

    PMID:20713885

    Open questions at the time
    • GEF responsible for plasma-membrane activation not identified
    • Did not resolve spatial dynamics relative to the synapse at molecular detail
  16. 2010 High

    Established N-RAS mutation as a clinically relevant mechanism of acquired B-RAF inhibitor resistance through MAPK reactivation.

    Evidence Resistant cell derivation, N-RAS knockdown and Q61K overexpression with MAPK readouts, validated in patient biopsies

    PMID:21107323

    Open questions at the time
    • Did not address combination strategies to overcome resistance
    • Other resistance routes not excluded
  17. 2011 Medium

    Connected plasma-membrane Toll-like receptor signaling to selective N-Ras activation driving IL-6 secretion and proliferation via a TRAF6-independent route.

    Evidence Isoform-selective Ras activation assays, RNAi of N-Ras and TRAF6, and IL-6 reporter/proliferation assays in cholangiocytes

    PMID:21757746

    Open questions at the time
    • The adaptor coupling TLRs to N-Ras unidentified
    • Single cell-type context
  18. 2011 Medium

    Showed the membrane is an active conformational partner that, with depalmitoylation and raft clustering, governs N-Ras conformation and plasma-membrane-to-cytoplasm exchange.

    Evidence Pressure-FTIR conformational analysis and patch-FRAP/EM with palmitoylation-deficient mutants and cholesterol depletion

    PMID:21807892 PMID:22203965

    Open questions at the time
    • FTIR conformer assignments lack mutagenesis follow-up
    • Single-lab biophysical methods
  19. 2012 High

    Defined a noncanonical mutant N-RAS survival pathway through STAT3, identifying MEK inhibition as a selective vulnerability in mutant-N-RAS colorectal tumors.

    Evidence Genetically engineered mouse model with STAT3 pathway analysis, MEK inhibition, and apoptosis assays

    PMID:23274911

    Open questions at the time
    • Direct molecular link from N-RAS to STAT3 not fully mapped
    • Generality beyond colorectal context untested here
  20. 2013 High

    Established palmitoylation as a strict requirement for agonist-driven N-Ras GTP loading and sustained mitogenic signaling.

    Evidence Palmitoylation-deficient mutants with GTP-loading assays, live-cell imaging, and palmitate content analysis of activated N-Ras

    PMID:23758196

    Open questions at the time
    • Did not identify the depalmitoylase governing the cycle
    • Spatial coordination with the palmitoyltransferase not resolved
  21. 2014 Medium

    Revealed a tumor-suppressive function of wild-type N-Ras/H-Ras in mutant-K-Ras cells, maintaining the ATR/Chk1 DNA damage checkpoint.

    Evidence RNAi knockdown with pathway phosphorylation analysis and chemosensitivity assays in vitro and in vivo

    PMID:24525237

    Open questions at the time
    • Mechanism connecting wild-type Ras to Chk1 Ser280 phosphorylation indirect
    • Single-lab study
  22. 2015 High

    Resolved the depalmitoylation arm of the trafficking cycle, identifying ABHD17 (not APT1/2) as the depalmitoylase driving N-Ras palmitate turnover and relocalization, and refined sub-Golgi distribution by acylation degree.

    Evidence Pulse-chase palmitate/protein half-life comparison, catalytic mutants, shRNA, and confocal/EM imaging of palmitoylation mutants

    PMID:25158650 PMID:26701913

    Open questions at the time
    • How ABHD17 is targeted to N-Ras pools not defined
    • Coupling of depalmitoylation kinetics to signaling output not quantified
  23. 2015 Medium

    Identified a unique, isoform-specific effector function in which wild-type N-Ras binds and activates cytoplasmic JAK2 to drive IL-8 secretion and tumor progression.

    Evidence N-RAS knockdown/overexpression, N-Ras·JAK2 co-IP, cytokine profiling, and in vivo tumor growth

    PMID:26166574

    Open questions at the time
    • Single-lab co-IP; direct binding interface not defined
    • Dependence on GTP state and membrane context untested
  24. 2016 Medium

    Linked specific N-RAS mutation classes to divergent signaling outputs and a CK2α vulnerability in codon-61 mutant melanoma.

    Evidence SILAC phosphoproteomics, kinase prediction, pharmacological CK2α inhibition, and patient sample validation

    PMID:27251789

    Open questions at the time
    • Mechanism by which Q61 versus G12 mutations bias pathway choice unresolved
    • Single-lab profiling
  25. 2016 High

    Identified VPS35/retromer as a cytosolic chaperone for farnesylated, non-palmitoylated N-Ras required for its GTP loading and oncogenic signaling.

    Evidence Affinity purification/MS, reciprocal co-IP with farnesyl/palmitoyl mutants, VPS35 silencing, and fractionation in melanoma cells

    PMID:27502489

    Open questions at the time
    • How VPS35 hands off N-Ras to the palmitoylation machinery not defined
    • Structural basis of farnesyl recognition unknown
  26. 2017 High

    Provided the structural and kinetic basis for isoform-specific behavior, showing N-Ras has distinct intrinsic hydrolysis kinetics set by allosteric features despite an identical active site.

    Evidence Enzyme kinetics with purified recombinant Ras isoforms and crystal structure of N-Ras bound to a GTP analogue

    PMID:28630043

    Open questions at the time
    • Allosteric residues responsible not functionally validated by mutagenesis
    • In-cell relevance of kinetic differences not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the spatial palmitoylation/depalmitoylation cycle, VPS35 chaperoning, and membrane-controlled conformations are integrated to dictate which effector arm (Raf/MEK/ERK, PI3K/AKT, JAK2, or STAT3) a given N-Ras mutant engages in a specific cellular context.
  • No unified spatiotemporal model linking trafficking machinery to effector selection
  • GEFs activating N-Ras at the plasma membrane downstream of TCR/TLR not identified
  • Mutation-class-specific effector bias mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0003924 GTPase activity 2 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2
Partners
ABHD17DHHC9GCP16GSNJAK2LGALS3RAF1VPS35
Complex memberships
VPS35/retromer (as bound cargo)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 A single nucleotide change at codon 61 of N-ras (glutamine to lysine substitution) activates its transforming potential, establishing that point mutations at codon 61 (and previously identified codon 12) are sufficient for oncogenic activation. Gene cloning, DNA sequencing, NIH 3T3 transformation assay Cell High 6616621
1985 Oncogenic N-ras (codon 61, glutamine to histidine) was cloned from a rhabdomyosarcoma cell line; a mutation at position 61 (CAA to CAT) is sufficient for transforming activity, confirming codon 61 as a key activation site. Gene cloning, chimeric recombinant construction, DNA sequencing, NIH 3T3 transformation assay International journal of cancer High 3158613
1985 Activation of N-ras in melanoma cells involves a codon 61 mutation (glutamine to lysine), and only clones carrying this mutation are biologically active in transfection assays. Southern blot, oligonucleotide hybridization, DNA sequencing, transfection/transformation assay Molecular and cellular biology High 3887133
1987 Normal and mutant (Gly-12, Asp-12, Val-12) human N-ras p21 proteins were produced in E. coli; mutant proteins showed reduced GTPase activity (Val-12 retains 12%, Asp-12 retains 43% of wild-type) while both were equally potent in inducing morphological transformation, indicating reduced GTPase rather than altered nucleotide binding drives oncogenicity. Recombinant protein production in E. coli, GTPase activity assay, guanine nucleotide binding assay, microinjection into NIH 3T3 cells Molecular and cellular biology High 3550423
1987 Oncogenic forms of N-ras (but not the proto-oncogenic form) completely suppress skeletal myoblast differentiation (fusion, muscle-specific gene expression including nicotinic acetylcholine receptor and creatine kinase) in C2 cells at the level of mRNA accumulation, independently of effects on cell proliferation. DNA-mediated gene transfer into mouse C2 skeletal muscle cells, analysis of muscle-specific mRNA and protein markers Molecular and cellular biology High 3600660
1997 In the presence of farnesyl protein transferase inhibitors, N-Ras (unlike H-Ras) is alternatively prenylated by geranylgeranyl transferase-1 and remains associated with the membrane fraction, explaining why FTIs fail to displace N-Ras from membranes. Cell-based prenylation assay in COS cells and DLD-1 colon carcinoma cells; membrane fractionation; FTI treatment The Journal of biological chemistry High 9162087
1997 S-palmitoylation of the farnesylated C-terminal peptide of N-ras stabilizes membrane association and mediates plasma membrane targeting; the S-acylated form localizes preferentially to the plasma membrane in CV-1 cells, and this localization is maintained by a 'kinetic trapping' mechanism at the plasma membrane itself, not through the secretory pathway. Fluorescent lipid-modified peptide reconstitution with liposomes, cell culture uptake assay, fluorescence microscopy, brefeldin A and low-temperature treatments Biochemistry High 9335573
1998 Ras-GRF/Cdc25Mm selectively activates Ha-Ras but not N-Ras or K-Ras 4B in vivo; the C-terminal hypervariable domain of Ras proteins dictates this GEF specificity, indicating that Ras isoforms can engage distinct upstream activators. In vivo Ras activation assay in cells, GEF selectivity assay, C-terminal domain analysis The Journal of biological chemistry Medium 9430727
1998 In Ha-ras-transformed fibroblasts, Raf-1 co-immunoprecipitates with endogenous c-N-Ras but not with (G12V)Ha-Ras, suggesting N-Ras has higher affinity for Raf-1 than Ha-Ras in vivo; antisense knockdown of c-N-Ras abrogates constitutive MAPK activity of Ha-ras-transformed cells, demonstrating that c-N-Ras function is required for Ha-Ras-driven MAPK signaling. Co-immunoprecipitation, antisense oligonucleotide knockdown, MAPK activity assay Oncogene Medium 9525741
1999 Transforming N-Ras(K61) mutant expression in NRK cells causes fragmentation and collapse of the Golgi complex, disruption of the actin cytoskeleton, and increased constitutive protein transport from the trans-Golgi network to the cell surface; these effects are partially inhibited by a phospholipase A2 inhibitor. Conditional expression system, electron microscopy, stereological analysis, protein transport assay, pharmacological inhibition Journal of cell science Medium 9914160
2001 Calmodulin binds to K-Ras but not to N-Ras or H-Ras, as demonstrated by calmodulin affinity chromatography; calmodulin inhibition preferentially activates K-Ras, not N-Ras. Calmodulin affinity chromatography from cellular lysates, Ras activation assay Molecular and cellular biology Medium 11585916
2005 DHHC9 and GCP16 form a protein complex that functions as a human protein palmitoyltransferase with substrate specificity for H-Ras and N-Ras but not for myristoylated Gαi1 or GAP-43; DHHC9 requires GCP16 for enzymatic activity and protein stability; the complex co-distributes in the Golgi apparatus. Purified DHHC9·GCP16 complex palmitoyltransferase assay in vitro, co-immunoprecipitation, subcellular localization by microscopy The Journal of biological chemistry High 16000296
2006 N-Ras lipidated protein partitions preferentially into liquid-disordered (ld) lipid domains rather than liquid-ordered (lo) or solid-ordered (so) domains, with the phase preference order ld > lo >> so; additionally, a large proportion localizes at the ld/lo phase boundary, suggesting an interfacial adsorption mechanism. Two-photon fluorescence microscopy on giant unilamellar vesicles, tapping-mode atomic force microscopy with fully lipidated (hexadecylated and farnesylated) fluorescent N-Ras protein Journal of the American Chemical Society High 16390147
2009 pRb inactivation induces E2F-dependent upregulation of farnesyl diphosphate synthase and prenyltransferases, leading to enhanced isoprenylation and activation of N-Ras; elevated N-Ras activity induces DNA damage response and p130-dependent cellular senescence in Rb-deficient cells. Genetic mouse model (Rb heterozygous), E2F-dependent gene expression analysis, N-Ras activity assay, senescence assays Cancer cell Medium 19345325
2010 Acquired resistance to PLX4032 (B-RAF V600E inhibitor) develops via N-RAS mutations (but not secondary B-RAF mutations), causing high levels of activated N-RAS that lead to significant MAPK pathway reactivation; knockdown of N-RAS reduced growth of resistant cells, and overexpression of N-RAS(Q61K) conferred PLX4032 resistance to sensitive cells. Drug-resistant cell line derivation, N-RAS mutation detection, N-RAS knockdown, N-RAS overexpression, MAPK pathway activity assays, validation in patient-derived biopsies Nature High 21107323
2011 TLR agonists at the plasma membrane (TLR 1, 2, 4, 5, 6) rapidly activate N-Ras but not other Ras isoforms in cholangiocytes; activated N-Ras signals through ERK1/2 to drive IL-6 secretion and cholangiocyte proliferation; TRAF6 depletion does not affect N-Ras activation, indicating a TRAF6-independent TLR-to-N-Ras pathway. Ras activation assay (isoform-selective), RNAi knockdown of N-Ras and TRAF6, luciferase reporter for IL-6 promoter, MEK/ERK inhibitors, proliferation assay The Journal of biological chemistry Medium 21757746
2011 Clustering of raft-associated proteins (GPI-anchored HA-GPI or fibronectin receptors) selectively enhances plasma membrane-to-cytoplasm exchange of GTP-bound N-Ras in a cholesterol-dependent manner; this effect depends strictly on depalmitoylation; HA-GPI clustering enhances Golgi accumulation and EGF-stimulated N-Ras-GTP signaling. Patch-FRAP, FRAP beam-size analysis, electron microscopy, cholesterol depletion, palmitoylation-deficient mutants Molecular and cellular biology High 21807892
2011 Membrane binding of lipidated N-Ras induces new conformational substates in the protein (detected as novel FTIR bands) beyond those induced by nucleotide binding; the membrane acts as an active interaction partner that controls G-domain orientation and selection of signaling conformations. Pressure-modulation FTIR spectroscopy, ATR-FTIR and IRRAS measurements on lipidated N-Ras in solution and membrane-bound states Proceedings of the National Academy of Sciences of the United States of America Medium 22203965
2012 Mutant N-RAS protects colorectal cancer cells from apoptosis via activation of a noncanonical MAPK pathway signaling through STAT3; MEK inhibition selectively induces apoptosis in colonic tumors expressing mutant N-RAS. Genetically engineered mouse model, STAT3 pathway analysis, MEK inhibitor treatment, apoptosis assays Cancer discovery High 23274911
2013 Palmitoylation of N-Ras is required for its activation by growth factor agonists; only palmitoylated N-Ras becomes GTP-loaded in response to EGF; palmitoylation-deficient N-Ras localizes to endomembranes, fails to be activated by agonists, and cannot sustain EGF- or serum-elicited mitogenic signaling. Palmitoylation-deficient N-Ras mutants, GTP-loading assay, live-cell Ras-GTP imaging, palmitate content analysis of activated N-Ras, dominant-negative Ras experiments The Biochemical journal High 23758196
2014 Wild-type H-Ras or N-Ras downregulation in mutant K-Ras cancer cells leads to hyperactivation of Erk/p90RSK and PI3K/Akt pathways and inhibitory phosphorylation of Chk1 at Ser280, abrogating ATR/Chk1 DNA damage checkpoint activation and sensitizing cells to DNA-damaging chemotherapeutics. RNAi knockdown, pathway phosphorylation analysis, Chk1 activity assays, chemotherapeutic sensitivity assays in vitro and in vivo Cancer cell Medium 24525237
2015 ABHD17 family proteins act as protein depalmitoylases that accelerate palmitate turnover on N-Ras; ABHD17 catalytic activity is required for N-Ras depalmitoylation and relocalization to internal cellular membranes. APT1 and APT2 inhibition (with Palmostatin B) does not affect palmitate turnover on N-Ras, whereas ABHD17 proteins do. Dual pulse-chase strategy comparing palmitate and protein half-lives, activity profiling, shRNA knockdown, catalytic mutant analysis eLife High 26701913
2015 Singly palmitoylated N-Ras is polarized within the Golgi with relative paucity at the trans-Golgi, in contrast to doubly palmitoylated H-Ras which distributes throughout Golgi stacks; palmitoylation mutants show that degree of acylation controls sub-Golgi distribution. Confocal live-cell fluorescent imaging, immunogold electron microscopy, palmitoylation mutant analysis Journal of cellular physiology High 25158650
2015 Wild-type N-Ras, but not K-Ras, induces IL-8 secretion by binding and activating the cytoplasmic pool of JAK2; IL-8 then acts in autocrine/paracrine fashion on cancer cells and stromal fibroblasts to promote basal-like breast cancer progression. N-RAS knockdown/overexpression, co-immunoprecipitation of N-Ras with JAK2, cytokine profiling, IL-8 reporter assays, in vivo tumor growth Cell reports Medium 26166574
2016 VPS35, a component of the retromer coat, binds to farnesylated but not palmitoylated N-Ras in the cytosol; this interaction is farnesyl-dependent and GTP-independent. VPS35 silencing increases N-Ras association with cytoplasmic vesicles, diminishes GTP loading of Ras, and inhibits MAPK signaling and growth of N-Ras-dependent melanoma cells. Affinity purification, mass spectrometry identification, co-immunoprecipitation, farnesyl/palmitoyl mutant analysis, VPS35 siRNA knockdown, subcellular fractionation The Journal of cell biology High 27502489
2017 N-Ras, H-Ras, and K-Ras show distinct intrinsic GTP hydrolysis rates under identical conditions; the presence of the Raf-RBD further differentiates isoform kinetics; crystal structure of N-Ras bound to a GTP analogue reveals structural features accounting for allosteric isoform-specific differences despite identical active sites. Enzyme kinetic assays with purified recombinant proteins, crystal structure determination of N-Ras·GTP analogue complex The Journal of biological chemistry High 28630043
2003 N-ras proto-oncogene suppresses the malignant phenotype: lack of wild-type N-ras alleles in mice favors thymic lymphoma development, while overexpression of wild-type N-ras protects against lymphomagenesis; introduction of wild-type N-ras into N-ras-deficient tumor cells decreases growth in low serum and soft agar. N-ras knockout mouse model, transgenic overexpression, in vitro growth assays Cancer research Medium 12154063
2003 N-ras is specifically required for normal T-cell function: N-ras knockout mice have reduced CD8 single positive thymocytes, decreased thymocyte proliferation, defective T-cell receptor Ras signaling activation, reduced IL-2 production upon activation, and increased susceptibility to influenza infection. N-ras knockout mouse model, flow cytometry, thymocyte proliferation assay, Ras signaling/activation assays, in vivo influenza challenge Cancer research High 12670913
2003 Deletion of N-ras rescues a unique subset of developmental defects (skeletal muscle differentiation, MCK gene expression) caused by Rb nullizygosity in mice, and potentiates MyoD transcriptional activity, demonstrating that N-ras and Rb operate in a common pathway controlling differentiation. Double knockout (Rb−/−; N-ras−/−) mouse model, histological analysis, MCK expression, MyoD transcriptional activity assay Molecular and cellular biology High 12861012
2006 N-RAS and H-RAS (but not K-RAS) are required for TGF-β1-mediated fibroblast proliferation and ECM synthesis regulation; H-ras−/−/N-ras−/− double knockout fibroblasts show increased ECM synthesis and decreased ERK activation, with compensatory Akt upregulation; MEK/ERK mediates Ras-dependent proliferation while PI3K-Akt mediates ECM synthesis control. Double knockout (H-ras−/−/N-ras−/−) mouse embryonic fibroblasts, TGF-β1 stimulation, ERK and Akt activation assays, pathway inhibitors, proliferation and ECM assays Experimental cell research Medium 16624289
2006 Endogenous N-RAS physically interacts with gelsolin; in cells expressing wild-type K-RAS, N-RAS subserves an antiapoptotic role that is compromised by the presence of oncogenic K-RAS; mutant K-RAS elevates GTP-bound N-RAS and alters modulation of the N-RAS:gelsolin complex following apoptotic challenge. Co-immunoprecipitation of endogenous N-RAS and gelsolin, isogenic cell lines with wild-type vs. mutant K-RAS, apoptosis assays Oncogene Medium 17130841
2008 Galectin-3 N-terminal domain interacts with and inhibits RasGRP4-mediated GTP loading specifically on N-Ras and H-Ras but not K-Ras; EGF-stimulated GTP loading of N-Ras is blocked in high Gal-3-expressing cells; PMA activation of RasGRPs or Gal-3 shRNA knockdown increases N-Ras-GTP levels. Co-immunoprecipitation, RasGRP4 GEF activity assay on N-Ras, Gal-3 shRNA knockdown, Ras activation assays Biochimica et biophysica acta Medium 18413234
2010 TCR-induced activation of endogenous Ras proceeds exclusively at the plasma membrane, not at the Golgi or other endomembranes; palmitoylation of N-Ras is critical for its activation by TCR signals, as palmitoylation-deficient N-Ras confined to endomembranes is not activated. Live-cell Ras-GTP imaging with novel affinity probes in Jurkat and primary T cells, palmitoylation-deficient Ras mutants, immunological synapse imaging Journal of immunology High 20713885
2011 H-ras and N-ras are dispensable for thymocyte development and mature T-cell activation but are critical controllers of Th1 responses: CD4+ T cells from H-ras- or N-ras-deficient mice show markedly decreased IFN-γ production and impaired T-bet induction after TCR stimulation; in vivo Th1 immunity against L. major is defective. H-ras−/− and N-ras−/− mouse models, T-cell activation assays, cytokine production, T-bet expression, in vivo L. major infection Blood High 21444916
2016 NRAS(G12V) mutant melanocytes display pronounced PI3K/AKT signaling while NRAS(Q61L) mutant melanocytes display pronounced MAPK signaling; CK2α is significantly overrepresented in NRAS(Q61) mutant cells and these cells are more sensitive to CK2α pharmacologic inhibition. SILAC-based phosphoproteomics, kinase prediction modeling, pharmacological CK2α inhibition, patient sample validation at mRNA and protein level The Journal of investigative dermatology Medium 27251789
1997 Transcription of unr (upstream of N-ras) negatively regulates N-ras expression in vivo through transcriptional interference; deletion of the unr promoter in mice increases N-ras mRNA accumulation by 20–65%. Homologous recombination deletion of unr promoter in mouse ES cells, RNase protection assays for N-ras mRNA levels FEBS letters Medium 9450542

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 1759 21107323
1997 K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. The Journal of biological chemistry 751 9162087
1983 Structure and activation of the human N-ras gene. Cell 534 6616621
1997 K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes & development 462 9334313
2005 DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras. The Journal of biological chemistry 290 16000296
2015 ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization. eLife 283 26701913
1987 Mutations in N-ras predominate in acute myeloid leukemia. Blood 255 3103719
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1997 S-Acylation and plasma membrane targeting of the farnesylated carboxyl-terminal peptide of N-ras in mammalian fibroblasts. Biochemistry 114 9335573
2017 The small GTPases K-Ras, N-Ras, and H-Ras have distinct biochemical properties determined by allosteric effects. The Journal of biological chemistry 109 28630043
2009 Rb Regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-ras isoprenylation. Cancer cell 105 19345325
1999 Mutational analysis of the N-ras, p53, p16INK4a, CDK4, and MC1R genes in human congenital melanocytic naevi. Journal of medical genetics 101 10465111
2006 Visualizing association of N-ras in lipid microdomains: influence of domain structure and interfacial adsorption. Journal of the American Chemical Society 98 16390147
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1985 Activation of N-ras in a human melanoma cell line. Molecular and cellular biology 91 3887133
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2001 H-, K-, and N-ras gene mutation in atypical fibroxanthoma and malignant fibrous histiocytoma. Human pathology 50 11727262
2013 GNA11 and N-RAS mutations: alternatives for MAPK pathway activating GNAQ mutations in primary melanocytic tumours of the central nervous system. Neuropathology and applied neurobiology 49 22758774
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2018 Neratinib and entinostat combine to rapidly reduce the expression of K-RAS, N-RAS, Gαq and Gα11 and kill uveal melanoma cells. Cancer biology & therapy 39 30571927
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2004 Transcriptional activation of H- and N-ras oncogenes in human cervical cancer. Gynecologic oncology 29 14984964
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2008 N-Ras or K-Ras inhibition increases the number and enhances the function of Foxp3 regulatory T cells. European journal of immunology 28 18461565
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1999 N-Ras induces alterations in Golgi complex architecture and in constitutive protein transport. Journal of cell science 27 9914160
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2016 Phosphoproteomic Analyses of NRAS(G12) and NRAS(Q61) Mutant Melanocytes Reveal Increased CK2α Kinase Levels in NRAS(Q61) Mutant Cells. The Journal of investigative dermatology 22 27251789
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