id: P01111
gene_symbol: NRAS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NRAS is one of the three canonical human RAS small GTPases (with HRAS and KRAS).
  It is a peripheral membrane protein anchored to the cytoplasmic face of cellular membranes
  through C-terminal lipidation (farnesylation at Cys-186 and palmitoylation at Cys-181) and
  functions as a binary molecular switch that binds GDP/GTP and possesses intrinsic GTPase
  activity. Cycling between an inactive GDP-bound and an active GTP-bound state under the control
  of guanine nucleotide exchange factors (GEFs such as SOS1 and RasGRP) and GTPase-activating
  proteins (GAPs), active GTP-bound NRAS transduces signals from receptor tyrosine kinases to
  downstream effectors, principally the RAF-MEK-ERK (MAPK) cascade and PI3K, thereby promoting
  cell proliferation, survival and differentiation. NRAS undergoes a constitutive
  de/re-palmitoylation acylation cycle that drives rapid shuttling between the plasma membrane
  and the Golgi apparatus, providing spatial control of signaling. Activating somatic and
  germline mutations at codons 12, 13 and 61 impair GTP hydrolysis and lock NRAS in its active
  state, a major oncogenic and developmental-disorder mechanism.
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: NRAS is a lipid-anchored peripheral membrane protein active on the cytoplasmic
      face of the plasma membrane, where GTP-bound NRAS engages RAF and other effectors.
      This is a core, well-supported phylogenetic localization for the RAS family.
    action: ACCEPT
    reason: Plasma membrane is the principal site of action for NRAS signaling and is strongly
      supported across orthologs (IBA) and by direct experimental evidence in human cells.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic side.'
    - reference_id: PMID:26701913
      supporting_text: ABHD17 catalytic activity is required for N-Ras depalmitoylation and
        re-localization to internal cellular membranes.
- term:
    id: GO:0007265
    label: Ras protein signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Ras protein signal transduction is the defining biological process of NRAS,
      which acts as a GTP/GDP-regulated switch transducing receptor tyrosine kinase input
      to downstream effectors (RAF-MEK-ERK, PI3K). Conserved across the RAS family.
    action: ACCEPT
    reason: This is the central core biological process for NRAS, supported phylogenetically
      (IBA) and by direct experimental evidence (see the IDA row for PMID:30712867).
    supported_by:
    - reference_id: PMID:30712867
      supporting_text: STK19 phosphorylates NRAS to enhance its binding to its downstream
        effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Active NRAS signaling through the MAPK and PI3K pathways promotes cell
      proliferation, and oncogenic NRAS mutations drive uncontrolled proliferation. This is a
      genuine but downstream consequence of NRAS signal transduction.
    action: KEEP_AS_NON_CORE
    reason: Promotion of proliferation is a real, conserved role of RAS GTPases but is a
      downstream physiological output of the core GTPase/signal-transduction function rather
      than the molecular activity itself. Retained as a non-core process.
    supported_by:
    - reference_id: PMID:30712867
      supporting_text: Activating mutations in NRAS account for 20%-30% of melanoma.
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: NRAS hydrolyzes GTP to GDP (EC 3.6.5.2), the catalytic activity underlying its
      switch behavior. Intrinsic GTPase activity is the canonical molecular function of all
      RAS-family proteins and is impaired by oncogenic codon-12/13/61 mutations.
    action: ACCEPT
    reason: GTPase activity is a core molecular function, supported phylogenetically (IBA) and
      directly (PMID:30712867; UniProt FUNCTION/CATALYTIC ACTIVITY).
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: Reaction=GTP + H2O = GDP + phosphate + H(+); ... EC=3.6.5.2
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: NRAS localizes to the Golgi apparatus membrane as part of its de/re-palmitoylation
      acylation cycle, shuttling between the plasma membrane and Golgi. UniProt subcellular
      location vocabulary maps to this term.
    action: ACCEPT
    reason: Golgi membrane is an experimentally supported core localization for NRAS (see EXP
      rows PMID:15705808, PMID:26701913); the UniProt SubCell IEA mapping is consistent.
    supported_by:
    - reference_id: PMID:15705808
      supporting_text: driving their rapid exchange between the plasma membrane (PM) and the
        Golgi apparatus.
- term:
    id: GO:0000165
    label: MAPK cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: NRAS is an upstream activator of the RAF-MEK-ERK MAPK cascade; GTP-bound NRAS
      recruits and activates RAF kinases, initiating the cascade.
    action: ACCEPT
    reason: MAPK cascade is a core biological process for NRAS, also supported by Reactome TAS
      (RAF/MAP kinase cascade) and by direct effector-binding evidence.
    supported_by:
    - reference_id: PMID:18641128
      supporting_text: eNOS selectively activates N-Ras but not K-Ras on the Golgi complex of
        T cells engaged with APC.
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro small-GTPase signature (IPR001806) maps NRAS to GTPase activity, its
      canonical catalytic molecular function.
    action: ACCEPT
    reason: Correct InterPro2GO mapping consistent with the IBA/IDA/ISS GTPase activity rows.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
- term:
    id: GO:0003925
    label: G protein activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: G protein activity is the EC-mapped (EC 3.6.5.2) molecular function for the small
      monomeric GTPase enzyme class. For NRAS this is the same underlying GTP-hydrolyzing
      activity captured more specifically as GTPase activity (GO:0003924).
    action: KEEP_AS_NON_CORE
    reason: The term is not wrong, but GTPase activity (GO:0003924) is the more standard and
      specific molecular-function descriptor for RAS proteins and is already present. Retained
      as a non-core duplicate of the core enzymatic activity rather than the preferred term.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: Reaction=GTP + H2O = GDP + phosphate + H(+); ... EC=3.6.5.2
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: NRAS binds GTP (and GDP) via its conserved P-loop and G-box motifs; nucleotide
      binding is the basis of its switch function. InterPro small-GTPase signatures map here.
    action: ACCEPT
    reason: GTP binding is a core molecular function directly supported by the crystal structure
      (GDP-bound) and the conserved GTP-binding sites in the UniProt record.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Plasma membrane localization of NRAS via the UniProt SubCell vocabulary mapping,
      consistent with its lipid-anchored peripheral membrane attachment.
    action: ACCEPT
    reason: Core localization, redundant with the IBA/IDA/EXP plasma membrane rows.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic side.'
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Generic signal transduction is correct for NRAS but is a broad parent of the more
      specific and better-supported Ras protein signal transduction (GO:0007265) and MAPK
      cascade (GO:0000165) annotations already present.
    action: KEEP_AS_NON_CORE
    reason: Not wrong, but less informative than the specific Ras-signal-transduction terms.
      Retained as a non-core broad classifier.
    supported_by:
    - reference_id: PMID:30712867
      supporting_text: STK19 phosphorylates NRAS to enhance its binding to its downstream
        effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Generic membrane localization from the InterPro small-GTPase mapping. NRAS is a
      membrane-anchored protein, but the specific plasma-membrane and Golgi-membrane terms are
      far more informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The bare membrane term loses the diagnostic plasma-membrane/Golgi-membrane
      specificity that is well established for NRAS.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic side.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18641128
  qualifier: enables
  review:
    summary: IntAct binary interaction (NRAS with RAF1/CRAF, P04049). This reflects NRAS
      binding its downstream RAF effector, consistent with its role activating the MAPK cascade,
      but it is captured only as the uninformative generic protein binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines. The
      biologically meaningful RAS-RAF effector engagement is already represented by the Ras
      protein signal transduction and MAPK cascade process annotations; the underlying study
      concerns eNOS-regulated N-Ras activation on the Golgi.
    supported_by:
    - reference_id: PMID:18641128
      supporting_text: eNOS selectively activates N-Ras but not K-Ras on the Golgi complex of
        T cells engaged with APC.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20080631
  qualifier: enables
  review:
    summary: IntAct binary interaction (NRAS with RAF1/CRAF, P04049) from a study of Ras
      membrane orientation and nanodomain localization. Captured as the generic protein binding
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative. The RAS-RAF effector interaction
      and membrane-nanodomain context are already represented by the signal-transduction and
      plasma-membrane annotations.
    supported_by:
    - reference_id: PMID:20080631
      supporting_text: Ras membrane orientation and nanodomain localization generate isoform
        diversity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21478863
  qualifier: enables
  review:
    summary: IntAct binary interactions (NRAS with RAF1 P04049, BRAF P15056, Braf P28028, Raf1
      Q99N57) from a study of ERK/PDE4-driven RAF isoform switching in melanoma. Reflects NRAS
      binding RAF effectors, captured only as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative. The RAS-RAF effector engagement
      is already represented by the Ras protein signal transduction and MAPK cascade processes.
    supported_by:
    - reference_id: PMID:21478863
      supporting_text: ERK and PDE4 cooperate to induce RAF isoform switching in melanoma.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IntAct interaction (NRAS with RIN1, Q13671) from a high-throughput interactome map
      defining protein communities and disease networks. Captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) from a large-scale interactome screen is
      uninformative as a molecular-function annotation; it does not define a specific NRAS
      activity beyond interactions already implied by its effector/regulator network.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities and
        disease networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30194290
  qualifier: enables
  review:
    summary: IntAct interactions (NRAS with RAF1 P04049 and BRAF P15056) from a study
      interrogating RAS-isoform interactomes (identified PIP5K1A as a KRAS-specific
      vulnerability). Reflects NRAS-RAF effector binding, captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative; the RAS-RAF effector interaction
      is already represented by the signal-transduction/MAPK annotations.
    supported_by:
    - reference_id: PMID:30194290
      supporting_text: Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A
        as a KRAS-specific vulnerability.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31209342
  qualifier: enables
  review:
    summary: IntAct interaction (NRAS with RABGGTB/GGTase component P49354) from the study
      identifying GGTase3, a geranylgeranyltransferase. Captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative. NRAS lipidation/prenylation is
      relevant to its membrane targeting, but this interaction is not by itself an informative
      molecular-function annotation.
    supported_by:
    - reference_id: PMID:31209342
      supporting_text: GGTase3 is a newly identified geranylgeranyltransferase targeting a
        ubiquitin ligase.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  qualifier: enables
  review:
    summary: IntAct interaction (NRAS with RAF1, P04049) from a study of EGFR-network rewiring
      in KRAS(G13D) colorectal cancer cells. Captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative; RAS-RAF effector engagement is
      already represented by the signal-transduction/MAPK annotations.
    supported_by:
    - reference_id: PMID:31980649
      supporting_text: Extensive rewiring of the EGFR network in colorectal cancer cells
        expressing transforming levels of KRAS(G13D).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: IntAct interactions (NRAS with RAF1 P04049, RAP1GDS1/SmgGDS P52306-5, RIN1 Q13671,
      RGL3 Q3MIN7, ARAF Q96II5) from a reference map of the human binary protein interactome.
      Includes genuine effectors/regulators but captured only as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) from a large binary interactome map is
      uninformative as a molecular function; the relevant effector/GEF interactions are already
      represented by the Ras signal-transduction annotations.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  qualifier: enables
  review:
    summary: IntAct interaction (NRAS with BRAF, P15056) from a kinase interaction network
      study. Reflects NRAS-RAF effector binding, captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative; the RAS-RAF effector interaction
      is already represented by the signal-transduction/MAPK annotations.
    supported_by:
    - reference_id: PMID:32707033
      supporting_text: Kinase Interaction Network Expands Functional and Disease Roles of Human
        Kinases.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: IntAct interaction (NRAS with PIK3R1 isoform P27986-2) from an interactome map of
      neurodegenerative disease proteins. PIK3R1 is the PI3K regulatory subunit, an NRAS
      effector arm, but captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative; the PI3K effector engagement is
      already implied by the Ras signal-transduction annotations.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease
        Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IntAct interaction (NRAS with RIN1, Q13671) from dual proteome-scale interactome
      networks. Captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) from a large-scale interactome screen is
      uninformative as a molecular-function annotation.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human
        interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34591642
  qualifier: enables
  review:
    summary: IntAct interactions (NRAS with RAF1 P04049, BRAF P15056, RIN1 Q13671) from a
      protein network map of head and neck cancer. Captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative; the RAS-RAF/effector interactions
      are already represented by the signal-transduction/MAPK annotations.
    supported_by:
    - reference_id: PMID:34591642
      supporting_text: A protein network map of head and neck cancer reveals PIK3CA mutant drug
        sensitivity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35512704
  qualifier: enables
  review:
    summary: IntAct interaction (NRAS with BRAF, P15056) from a study of mutation-directed
      neo-protein-protein interactions in cancer. Captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative; the RAS-RAF effector interaction
      is already represented by the signal-transduction/MAPK annotations.
    supported_by:
    - reference_id: PMID:35512704
      supporting_text: Systematic discovery of mutation-directed neo-protein-protein
        interactions in cancer.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35839996
  qualifier: enables
  review:
    summary: IntAct interactions (NRAS with RAF1 P04049, RABGGTB P49354, and Q96JH8) from a
      proteomic study of isoform-specific and nucleotide-dependent RAS interactions. Captured
      as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative; nucleotide-dependent effector
      interactions are already represented by the Ras signal-transduction annotations.
    supported_by:
    - reference_id: PMID:35839996
      supporting_text: A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent
        RAS Interactions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: IntAct interaction (NRAS with RIN1, Q13671) from a multimodal cell-map study.
      Captured as generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) from a large-scale mapping study is uninformative
      as a molecular-function annotation.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional
        genomics.
- term:
    id: GO:0000165
    label: MAPK cascade
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5673001
  qualifier: involved_in
  review:
    summary: Reactome places NRAS in the RAF/MAP kinase cascade, consistent with its core role
      as an upstream activator of RAF-MEK-ERK signaling.
    action: ACCEPT
    reason: Core biological process, concordant with the IEA MAPK cascade row and effector-binding
      evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-5673001
      supporting_text: RAF/MAP kinase cascade.
- term:
    id: GO:0046579
    label: positive regulation of Ras protein signal transduction
  evidence_type: NAS
  original_reference_id: PMID:35831509
  qualifier: involved_in
  review:
    summary: Active GTP-bound NRAS binds the SHOC2-PP1C holophosphatase complex, which
      dephosphorylates inhibitory sites on RAF to promote RAF activation, positively regulating
      Ras/MAPK signaling. This NAS annotation derives from the ComplexPortal SHOC2-NRAS-PPP1CA
      complex.
    action: KEEP_AS_NON_CORE
    reason: This represents NRAS participation in a positive-feedback/effector-activation complex
      rather than its core intrinsic GTPase switch activity. It is a valid, more specialized
      process, retained as non-core.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: Interacts (active GTP-bound form) with both SHOC2 and PP1c (all isoforms)
        to form a tertiary complex; SHOC2 and PP1c preferably bind M-Ras/MRAS, but they also bind
        K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (Human Protein Atlas) localizes NRAS to the plasma membrane,
      consistent with its lipid-anchored membrane attachment.
    action: ACCEPT
    reason: Direct (IDA) support for the core plasma-membrane localization.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic side.'
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:15705808
  qualifier: located_in
  review:
    summary: NRAS is experimentally localized to the Golgi apparatus membrane, where the
      de/re-palmitoylation acylation cycle traps farnesylated Ras before redirection to the
      plasma membrane.
    action: ACCEPT
    reason: Direct experimental support for core Golgi-membrane localization as part of the
      PM-Golgi shuttling cycle.
    supported_by:
    - reference_id: PMID:15705808
      supporting_text: Depalmitoylation redistributes farnesylated Ras in all membranes,
        followed by repalmitoylation and trapping of Ras at the Golgi, from where it is
        redirected to the PM via the secretory pathway.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:26701913
  qualifier: located_in
  review:
    summary: NRAS localizes to Golgi/internal membranes, with ABHD17 depalmitoylase activity
      controlling its palmitate turnover and relocalization between plasma membrane and internal
      membranes.
    action: ACCEPT
    reason: Direct experimental support for core Golgi-membrane localization in the context of
      palmitoylation-dependent trafficking.
    supported_by:
    - reference_id: PMID:26701913
      supporting_text: ABHD17 catalytic activity is required for N-Ras depalmitoylation and
        re-localization to internal cellular membranes.
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: GTPase activity transferred by sequence similarity from KRAS (P01116). NRAS shares
      the canonical RAS catalytic machinery and intrinsic GTPase activity.
    action: ACCEPT
    reason: Correct similarity-based assignment of the core GTPase molecular function, fully
      concordant with the IBA/IDA evidence.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:15705808
  qualifier: located_in
  review:
    summary: NRAS is experimentally localized to the plasma membrane, the principal signaling
      site, as part of the PM-Golgi acylation shuttling cycle.
    action: ACCEPT
    reason: Direct experimental support for the core plasma-membrane localization.
    supported_by:
    - reference_id: PMID:15705808
      supporting_text: driving their rapid exchange between the plasma membrane (PM) and the
        Golgi apparatus.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:26701913
  qualifier: located_in
  review:
    summary: NRAS plasma-membrane localization is palmitoylation-dependent; ABHD17 depalmitoylase
      activity drives N-Ras relocalization from the plasma membrane to internal membranes, and
      loss of palmitoylation (Cys181Ser) abolishes plasma-membrane localization.
    action: ACCEPT
    reason: Direct experimental support for the core plasma-membrane localization.
    supported_by:
    - reference_id: PMID:26701913
      supporting_text: ABHD17 catalytic activity is required for N-Ras depalmitoylation and
        re-localization to internal cellular membranes.
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9649736
  qualifier: enables
  review:
    summary: Reactome attributes GTPase activity to NRAS, its canonical catalytic molecular
      function.
    action: ACCEPT
    reason: Concordant with the core GTPase activity annotations (IBA/IDA/ISS/IEA).
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647980
  qualifier: located_in
  review: &golgi_tas
    summary: Reactome RAS-processing/localization events place NRAS at the Golgi apparatus
      membrane, a bona-fide localization in its PM-Golgi shuttling cycle.
    action: ACCEPT
    reason: Concordant with the experimentally supported core Golgi-membrane localization.
    supported_by:
    - reference_id: PMID:15705808
      supporting_text: driving their rapid exchange between the plasma membrane (PM) and the
        Golgi apparatus.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647982
  qualifier: located_in
  review: *golgi_tas
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647977
  qualifier: located_in
  review: &er_tas
    summary: Reactome RAS-processing events localize NRAS to the endoplasmic reticulum membrane,
      where post-translational CAAX processing (RCE1/ICMT) of newly farnesylated Ras occurs en
      route to the Golgi and plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: ER membrane is a transient processing/transit site rather than the principal signaling
      location (plasma membrane/Golgi). Retained as a non-core localization supported only by
      Reactome pathway knowledge.
    supported_by:
    - reference_id: PMID:15705808
      supporting_text: from where it is redirected to the PM via the secretory pathway.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647978
  qualifier: located_in
  review: *er_tas
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647982
  qualifier: located_in
  review: *er_tas
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647999
  qualifier: located_in
  review: *er_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1168636
  qualifier: located_in
  review: &pm_tas
    summary: Reactome maps NRAS as a participant located at the plasma membrane across numerous
      RTK-to-RAS activation and RAF/MAPK signaling reactions. Plasma membrane is the principal,
      well-supported localization for NRAS.
    action: ACCEPT
    reason: The plasma-membrane localization is correct and is the core signaling site. The many
      Reactome rows are redundant reaction-level participations that all assert the same
      cellular-component placement.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic side.'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1225951
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1225957
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1250383
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1306972
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1433471
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-170986
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-177938
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-177945
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-186834
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-210977
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2179407
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2424477
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-392054
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5218845
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5621573
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5624486
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5624492
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5624494
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5637806
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5637808
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5654392
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5654402
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5654413
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5654426
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5654600
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5654618
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5654647
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5654663
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655241
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655277
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655326
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655347
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5658231
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5658435
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672950
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672965
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672966
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672969
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672972
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672973
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672978
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5672980
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5674018
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5674022
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5675417
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5675431
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5675433
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802837
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8851827
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8851877
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8851899
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8941613
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8941618
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8941623
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8941628
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8981353
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8981355
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9607304
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9632906
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9632918
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9634418
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647980
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647994
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9649733
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9649735
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9649736
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9653108
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9656209
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9656211
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9656212
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9656213
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9656214
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9656215
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9657599
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9657603
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9657606
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9657608
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9658253
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664991
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9665009
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9665404
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9665408
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9665700
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9665707
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9670436
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9672163
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9672170
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9695853
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9703441
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9647978
  qualifier: located_in
  review:
    summary: Reactome localizes newly synthesized, pre-processed (farnesylated but not yet
      membrane-anchored) NRAS to the cytosol during RAS processing.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization applies transiently to nascent unprocessed NRAS; the mature,
      functionally active protein is membrane-anchored. Retained as a non-core processing-stage
      location.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic side.'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802834
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802908
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802918
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802922
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802924
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802925
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802926
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802937
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802941
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802942
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802943
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6803233
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6803234
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6803240
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8936731
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9651280
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IDA
  original_reference_id: PMID:30712867
  qualifier: enables
  review:
    summary: Direct experimental study of NRAS function, including characterization of the
      oncogenic Q61R variant and STK19-mediated Ser-89 phosphorylation; UniProt cites this work
      (ECO:0000269|PubMed:30712867) for NRAS GDP/GTP binding and intrinsic GTPase activity.
    action: ACCEPT
    reason: Provides direct experimental (IDA) support for the core GTPase molecular function of
      NRAS.
    supported_by:
    - reference_id: file:human/NRAS/NRAS-uniprot.txt
      supporting_text: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
        {ECO:0000269|PubMed:30712867}.
- term:
    id: GO:0007265
    label: Ras protein signal transduction
  evidence_type: IDA
  original_reference_id: PMID:30712867
  qualifier: involved_in
  review:
    summary: NRAS transduces signals to downstream effectors; STK19 phosphorylates NRAS at
      Ser-89 to enhance effector binding and promote oncogenic NRAS-driven melanocyte
      transformation, providing direct evidence for NRAS signal transduction.
    action: ACCEPT
    reason: Direct experimental (IDA) support for the core Ras-protein-signal-transduction
      process.
    supported_by:
    - reference_id: PMID:30712867
      supporting_text: STK19 phosphorylates NRAS to enhance its binding to its downstream
        effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation.
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:23209302
  qualifier: enables
  review:
    summary: This annotation derives from a study focused on KIF14 and Rap1a-Radil signaling in
      breast cancer; NRAS is not the subject of that work, and the protein-containing complex
      binding term is generic.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited paper does not characterize a specific NRAS molecular function; the generic
      complex-binding term adds little beyond NRAS's established effector/regulator interactions
      already captured by its signal-transduction annotations.
    supported_by:
    - reference_id: PMID:23209302
      supporting_text: KIF14 negatively regulates Rap1a-Radil signaling during breast cancer
        progression.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IMP
  original_reference_id: PMID:23619365
  qualifier: involved_in
  review:
    summary: In endothelial cells, miR-146a downregulates NRAS and thereby attenuates
      angiogenesis, implying that NRAS normally supports endothelial cell proliferation and
      angiogenesis. This is a tissue-specific downstream output of NRAS/MAPK signaling.
    action: KEEP_AS_NON_CORE
    reason: The role in endothelial cell proliferation is a peripheral, cell-type-specific
      consequence of the core NRAS signaling function rather than its defining activity. Retained
      as a non-core process.
    supported_by:
    - reference_id: PMID:23619365
      supporting_text: which attenuated angiogenesis through downregulation of NRAS.
- term:
    id: GO:0070821
    label: tertiary granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798747
  qualifier: located_in
  review:
    summary: This Reactome annotation (neutrophil degranulation pathway) places NRAS at the
      tertiary granule membrane in neutrophils. It reflects pathway-level granule-proteome
      membership rather than a core functional localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tertiary granule membrane is a cell-type-specific membrane compartment derived from
      a degranulation proteome pathway; it is far less informative than the established plasma
      membrane/Golgi localizations and does not represent the core site of NRAS signaling.
    supported_by:
    - reference_id: Reactome:R-HSA-6798747
      supporting_text: Neutrophil degranulation.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: NRAS was detected in a high-throughput NK-cell membrane proteome. Generic membrane
      localization is consistent with NRAS being a membrane-anchored protein but is much less
      informative than its specific plasma-membrane/Golgi-membrane localizations.
    action: MARK_AS_OVER_ANNOTATED
    reason: The bare membrane term from a proteomic dataset loses the diagnostic
      plasma-membrane/Golgi specificity already well established for NRAS.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: Defining the membrane proteome of NK cells.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: NRAS was detected in a proteomic survey of B-cell exosomes. This is a
      high-throughput co-purification rather than evidence of a functional exosomal role.
    action: MARK_AS_OVER_ANNOTATED
    reason: Exosomal detection of a membrane-anchored signaling GTPase likely reflects membrane
      co-isolation; it does not represent a core localization or function and over-annotates the
      established plasma-membrane/Golgi biology.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: MHC class II-associated proteins in B-cell exosomes and potential
        functional implications for exosome biogenesis.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798747
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802914
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802915
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802916
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802919
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6802921
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6803230
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8936676
  qualifier: located_in
  review: *pm_tas
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:21968647
  qualifier: part_of
  review:
    summary: NRAS localizes to and is activated at the Golgi apparatus; the Golgi-resident
      proteins PAQR10/PAQR11 interact with NRAS and elevate its Golgi localization and activation,
      providing direct evidence for Golgi localization.
    action: ACCEPT
    reason: Direct experimental support for the core Golgi-apparatus localization, consistent
      with the Golgi-membrane annotations and the PM-Golgi shuttling model. (The part_of qualifier
      is atypical for an organelle localization, but the underlying Golgi localization is sound.)
    supported_by:
    - reference_id: PMID:21968647
      supporting_text: Overexpression of PAQR10/PAQR11 markedly elevates Golgi localization of
        HRas, NRas and KRas4A, but not KRas4B.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:15705808
  title: An acylation cycle regulates localization and activity of palmitoylated Ras
    isoforms.
  findings:
  - statement: A constitutive de/re-palmitoylation acylation cycle drives rapid exchange of
      N-Ras between the plasma membrane and the Golgi apparatus.
    supporting_text: the specific subcellular distribution of H- and Nras guanosine triphosphate-binding
      proteins is generated by a constitutive de/reacylation cycle that operates on palmitoylated
      proteins, driving their rapid exchange between the plasma membrane (PM) and the Golgi apparatus.
- id: PMID:18641128
  title: Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi
    complex of antigen-stimulated T cells.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20080631
  title: Ras membrane orientation and nanodomain localization generate isoform diversity.
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  findings: []
- id: PMID:21478863
  title: ERK and PDE4 cooperate to induce RAF isoform switching in melanoma.
  findings: []
- id: PMID:21968647
  title: PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus.
  findings:
  - statement: NRAS localizes to and is activated at the Golgi apparatus; Golgi-resident
      PAQR10/PAQR11 bind NRAS and elevate its Golgi localization and activation.
    supporting_text: Overexpression of PAQR10/PAQR11 markedly elevates Golgi localization of
      HRas, NRas and KRas4A, but not KRas4B.
- id: PMID:23209302
  title: KIF14 negatively regulates Rap1a-Radil signaling during breast cancer progression.
  findings: []
- id: PMID:23619365
  title: MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy.
  findings:
  - statement: NRAS is a target of miR-146a in endothelial cells; miR-146a downregulates NRAS
      and attenuates angiogenesis, implicating NRAS in endothelial cell proliferation.
    supporting_text: which attenuated angiogenesis through downregulation of NRAS.
- id: PMID:26701913
  title: ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate
    turnover and subcellular localization.
  findings:
  - statement: ABHD17 depalmitoylase activity controls N-Ras palmitate turnover and
      relocalization between plasma membrane and internal membranes.
    supporting_text: ABHD17 catalytic activity is required for N-Ras depalmitoylation and
      re-localization to internal cellular membranes.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:30194290
  title: Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A
    as a KRAS-specific vulnerability.
  findings: []
- id: PMID:30712867
  title: Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis.
  findings:
  - statement: STK19 phosphorylates NRAS at Ser-89 to enhance binding to downstream effectors,
      promoting oncogenic NRAS signaling; provides direct evidence for NRAS GTPase/signal
      transduction function.
    supporting_text: STK19 phosphorylates NRAS to enhance its binding to its downstream effectors
      and promotes oncogenic NRAS-mediated melanocyte malignant transformation.
  - statement: Activating NRAS mutations are common in melanoma.
    supporting_text: Activating mutations in NRAS account for 20%-30% of melanoma.
- id: PMID:31209342
  title: GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin
    ligase.
  findings: []
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing
    transforming levels of KRAS(G13D).
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human
    Kinases.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34591642
  title: A protein network map of head and neck cancer reveals PIK3CA mutant drug
    sensitivity.
  findings: []
- id: PMID:35512704
  title: Systematic discovery of mutation-directed neo-protein-protein interactions
    in cancer.
  findings: []
- id: PMID:35831509
  title: Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex.
  findings:
  - statement: Active GTP-bound NRAS (like other RAS isoforms) can bind SHOC2 and PP1C to form a
      holophosphatase complex that promotes RAF activation and positively regulates Ras/MAPK
      signaling.
    supporting_text: SHOC2 and PP1c preferably bind M-Ras/MRAS, but they also bind K-Ras/KRAS,
      N-Ras/NRAS and H-Ras/HRAS
- id: PMID:35839996
  title: A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent
    RAS Interactions.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-1168636
  title: p-RasGRP1,3:DAG cause RAS to exchange GDP for GTP
  findings: []
- id: Reactome:R-HSA-1225951
  title: SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex
    with ligand-responsive p-6Y-EGFR mutants)
  findings: []
- id: Reactome:R-HSA-1225957
  title: SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex
    with phosphorylated SHC1 and ligand-responsive p-6Y-EGFR mutants)
  findings: []
- id: Reactome:R-HSA-1250383
  title: RAS guanyl-nucleotide exchange mediated by SOS1 in complex with GRB2 and
    p-Y349,350-SHC1:p-ERBB4
  findings: []
- id: Reactome:R-HSA-1306972
  title: RAS guanyl nucleotide exchange mediated by SOS1 bound to GRB2 in complex
    with phosphorylated ERBB4:ERBB2 heterodimers
  findings: []
- id: Reactome:R-HSA-1433471
  title: Activation of RAS by p-KIT bound SOS1
  findings: []
- id: Reactome:R-HSA-170986
  title: Ral-GDS binds to Ras-GTP
  findings: []
- id: Reactome:R-HSA-177938
  title: SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:GRB2:SOS1)
  findings: []
- id: Reactome:R-HSA-177945
  title: SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:SHC1:GRB2:SOS1)
  findings: []
- id: Reactome:R-HSA-186834
  title: SOS-mediated nucleotide exchange on RAS (PDGF receptor:GRB2:SOS)
  findings: []
- id: Reactome:R-HSA-210977
  title: Sos-mediated nucleotide exchange of Ras (Tie2 receptor:Grb2:Sos)
  findings: []
- id: Reactome:R-HSA-2179407
  title: SOS1-mediated nucleotide exchange of RAS (HB-EFG-initiated)
  findings: []
- id: Reactome:R-HSA-2424477
  title: SOS mediated nucleotide exchange of RAS (SHC)
  findings: []
- id: Reactome:R-HSA-392054
  title: NCAM1:pFAK:Grb2:Sos-mediated nucleotide exchange of Ras
  findings: []
- id: Reactome:R-HSA-5218845
  title: p-SPHK1 phosphorylates sphingosine to sphingosine 1-phosphate
  findings: []
- id: Reactome:R-HSA-5621573
  title: CD209 activate GTPase RAS
  findings: []
- id: Reactome:R-HSA-5624486
  title: SFKs phosphorylates RAF1 on Y340,Y341
  findings: []
- id: Reactome:R-HSA-5624492
  title: PAK phosphorylates p21 RAF1 on S338
  findings: []
- id: Reactome:R-HSA-5624494
  title: RAF1 binds p21 RAS:GTP
  findings: []
- id: Reactome:R-HSA-5637806
  title: SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex
    with p-EGFRvIII)
  findings: []
- id: Reactome:R-HSA-5637808
  title: SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex
    with phosphorylated SHC1 and p-EGFRvIII)
  findings: []
- id: Reactome:R-HSA-5654392
  title: Activated FGFR1:p-FRS:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5654402
  title: Activated FGFR2:p-SHC1:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5654413
  title: Activated FGFR3:p-FRS2:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5654426
  title: Activated FGFR4:p-SHC1:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5654600
  title: Activated FGFR1:p-SHC1:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5654618
  title: Activated FGFR2:p-FRS2:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5654647
  title: Activated FGFR3:p-SHC1:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5654663
  title: Activated FGFR4:p-FRS2:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5655241
  title: Activated FGFR2 mutants:p-FRS2:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5655277
  title: Activated FGFR3 point, translocation and fusion mutants:p-FRS2:GRB2:SOS1
    activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5655326
  title: Activated FGFR1 mutants:p-FRS2:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5655347
  title: Activated FGFR4 mutants:p-FRS2:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5658231
  title: RAS GAPs stimulate RAS GTPase activity
  findings: []
- id: Reactome:R-HSA-5658435
  title: RAS GAPs bind RAS:GTP
  findings: []
- id: Reactome:R-HSA-5672950
  title: '"Activator" RAF:YWHAB dimer binds RAS:GTP'
  findings: []
- id: Reactome:R-HSA-5672965
  title: RAS GEFs promote RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-5672966
  title: RAS:GTP:'activator' RAF homo/heterodimerizes with other RAF monomers
  findings: []
- id: Reactome:R-HSA-5672969
  title: Phosphorylation of RAF
  findings: []
- id: Reactome:R-HSA-5672972
  title: MAP2Ks and MAPKs bind to the activated RAF complex
  findings: []
- id: Reactome:R-HSA-5672973
  title: MAP2Ks phosphorylate MAPKs
  findings: []
- id: Reactome:R-HSA-5672978
  title: RAF phosphorylates MAP2K dimer
  findings: []
- id: Reactome:R-HSA-5672980
  title: Dissociation of RAS:RAF complex
  findings: []
- id: Reactome:R-HSA-5673001
  title: RAF/MAP kinase cascade
  findings: []
- id: Reactome:R-HSA-5674018
  title: BRAP binds RAS:GTP
  findings: []
- id: Reactome:R-HSA-5674022
  title: BRAP autoubiquitinates
  findings: []
- id: Reactome:R-HSA-5675417
  title: PEBP1 binds activated RAF1
  findings: []
- id: Reactome:R-HSA-5675431
  title: PP2A dephosphorylates RAF1
  findings: []
- id: Reactome:R-HSA-5675433
  title: PP5 dephosphorylates RAF1 S338
  findings: []
- id: Reactome:R-HSA-6798747
  title: Exocytosis of tertiary granule membrane proteins
  findings: []
- id: Reactome:R-HSA-6802834
  title: RAS GTPase mutants don't hydrolyze GTP
  findings: []
- id: Reactome:R-HSA-6802837
  title: Loss-of-function NF1 variants don't stimulate RAS GTPase activity
  findings: []
- id: Reactome:R-HSA-6802908
  title: RAS mutants bind inactive RAF
  findings: []
- id: Reactome:R-HSA-6802914
  title: RAS:GTP:moderate kinase activity p-RAF complexes bind MAP2Ks and MAPKs
  findings: []
- id: Reactome:R-HSA-6802915
  title: Moderate kinase activity BRAF mutants bind RAS:GTP
  findings: []
- id: Reactome:R-HSA-6802916
  title: RAF is phosphorylated downstream of moderate kinase activity BRAF mutants
  findings: []
- id: Reactome:R-HSA-6802918
  title: Activated MAP2Ks phosphorylate MAPKs downstream of inactive BRAF mutants
  findings: []
- id: Reactome:R-HSA-6802919
  title: RAS:GTP:moderate kinase activity p-RAF complexes phosphorylate MAP2Ks
  findings: []
- id: Reactome:R-HSA-6802921
  title: Activated MAP2Ks phosphorylate MAPKs downstream of moderate kinase activity
    BRAF mutants
  findings: []
- id: Reactome:R-HSA-6802922
  title: Activated MAP2Ks phosphorylate MAPKs downstream of oncogenic RAS
  findings: []
- id: Reactome:R-HSA-6802924
  title: RAF is phosphorylated downstream of oncogenic RAS
  findings: []
- id: Reactome:R-HSA-6802925
  title: Mutant RAS:p-RAF complexes bind MAP2Ks and MAPKs
  findings: []
- id: Reactome:R-HSA-6802926
  title: Mutant RAS:p-RAF complexes phosphorylate MAP2Ks
  findings: []
- id: Reactome:R-HSA-6802937
  title: Inactive BRAF mutants bind mutant RAS:GTP
  findings: []
- id: Reactome:R-HSA-6802941
  title: RAF is paradoxically phosphorylated downstream of kinase-inactive RAF
  findings: []
- id: Reactome:R-HSA-6802942
  title: RAS:GTP:p-RAF complexes paradoxically bind MAP2Ks and MAPKs
  findings: []
- id: Reactome:R-HSA-6802943
  title: RAS:GTP:inactive p-RAF complexes phosphorylate MAP2Ks
  findings: []
- id: Reactome:R-HSA-6803230
  title: Dissociation of moderate activity BRAF complexes
  findings: []
- id: Reactome:R-HSA-6803233
  title: Dissociation of oncogenic RAS:RAF complex
  findings: []
- id: Reactome:R-HSA-6803234
  title: Dissociation of paradoxically activated RAS:BRAF complexes
  findings: []
- id: Reactome:R-HSA-6803240
  title: Homo- or heterodimerization of RAF downstream of mutant RAS
  findings: []
- id: Reactome:R-HSA-8851827
  title: RAS guanyl nucleotide exchange by MET-bound GRB2:SOS1
  findings: []
- id: Reactome:R-HSA-8851877
  title: RAS guanyl nucleotide exchange by SOS1 associated with RANBP9 and MET
  findings: []
- id: Reactome:R-HSA-8851899
  title: RAS guanyl nucleotide exchange by SOS1 bound to GRB2, SCH1-2 and MET
  findings: []
- id: Reactome:R-HSA-8936676
  title: Moderate kinase activity BRAF mutants:RAS:GTP homo/heterodimerize
  findings: []
- id: Reactome:R-HSA-8936731
  title: Inactive BRAF mutants:mutant RAS:GTP bind RAF1
  findings: []
- id: Reactome:R-HSA-8941613
  title: Activated FGFR4:p-FRS:p-PTPN11 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-8941618
  title: Activated FGFR2:p-FRS:p-PTPN11 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-8941623
  title: Activated FGFR1:p-FRS:p-PTPN11 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-8941628
  title: Activated FGFR3:p-FRS:p-PTPN11 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-8981353
  title: RASA1 stimulates RAS GTPase activity
  findings: []
- id: Reactome:R-HSA-8981355
  title: RASA1 binds RAS:GTP
  findings: []
- id: Reactome:R-HSA-9607304
  title: SOS1-mediated nucleotide exchange of RAS downstream of FLT3
  findings: []
- id: Reactome:R-HSA-9632906
  title: PRKCZ recruits RAS in response to estrogen stimulation
  findings: []
- id: Reactome:R-HSA-9632918
  title: PRKCZ stimulates RAS nucleotide exchange in response to estrogen
  findings: []
- id: Reactome:R-HSA-9634418
  title: RAS guanyl-nucleotide exchange mediated by SOS1 in complex with GRB2 and
    ERBB2 homodimer:p-SHC1
  findings: []
- id: Reactome:R-HSA-9647977
  title: ICMT methylates S-Farn RAS proteins
  findings: []
- id: Reactome:R-HSA-9647978
  title: pro-RAS proteins are farnesylated
  findings: []
- id: Reactome:R-HSA-9647980
  title: mature RAS proteins translocate to plasma membrane
  findings: []
- id: Reactome:R-HSA-9647982
  title: S-farn Me-HRAS, -NRAS and -KRAS4A are palmitoylated
  findings: []
- id: Reactome:R-HSA-9647994
  title: RAS proteins are depalmitoylated
  findings: []
- id: Reactome:R-HSA-9647999
  title: RCE1 cleaves S-Farn proRAS proteins
  findings: []
- id: Reactome:R-HSA-9649733
  title: mature p21 RAS binds GDP
  findings: []
- id: Reactome:R-HSA-9649735
  title: Intrinsic nucleotide exchange on RAS
  findings: []
- id: Reactome:R-HSA-9649736
  title: RAS intrinsic GTPase activity hydrolyzes GTP to GDP
  findings: []
- id: Reactome:R-HSA-9651280
  title: RAS GAP mutants aren't stimulated by GAPs
  findings: []
- id: Reactome:R-HSA-9653108
  title: Raf dimer inhibitors bind RAF heterodimers
  findings: []
- id: Reactome:R-HSA-9656209
  title: Dissociation of RAS:RAF1 mutant complex
  findings: []
- id: Reactome:R-HSA-9656211
  title: MAP2Ks and MAPKs bind to the activated mutant RAF1 complex
  findings: []
- id: Reactome:R-HSA-9656212
  title: Phosphorylation of RAF1 mutants
  findings: []
- id: Reactome:R-HSA-9656213
  title: RAF1 mutants show enhanced heterodimerization with BRAF
  findings: []
- id: Reactome:R-HSA-9656214
  title: MAP2Ks phosphorylate MAPKs downstream of RAF1 mutants
  findings: []
- id: Reactome:R-HSA-9656215
  title: RAF1 mutant complexes phosphorylate MAP2K dimer
  findings: []
- id: Reactome:R-HSA-9657599
  title: Dual mechanism MAP2K inhibitors bind MAP2Ks
  findings: []
- id: Reactome:R-HSA-9657603
  title: Dual mechanism MAPK inhibitors bind MAPKs
  findings: []
- id: Reactome:R-HSA-9657606
  title: Single mechanism MAP2K inhibitors bind phosphorylated MAP2Ks
  findings: []
- id: Reactome:R-HSA-9657608
  title: Single mechanism MAPK inhibitors bind phosphorylated MAPK
  findings: []
- id: Reactome:R-HSA-9658253
  title: RAS:GTP binds PI3K
  findings: []
- id: Reactome:R-HSA-9664991
  title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 KD mutants
  findings: []
- id: Reactome:R-HSA-9665009
  title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 KD mutants
    and EGFR
  findings: []
- id: Reactome:R-HSA-9665404
  title: RAS guanyl nucleotide exchange mediated by the p-6Y- ERBB2 ECD mutants:EGF:p-6Y-EGFR:p-SHC1:GRB2:SOS1
  findings: []
- id: Reactome:R-HSA-9665408
  title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 ECD
    mutants and EGFR through GRB2
  findings: []
- id: Reactome:R-HSA-9665700
  title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 TMD/JMD
    mutants
  findings: []
- id: Reactome:R-HSA-9665707
  title: RAS activation by SOS1 bound to phosphorylated heterodimers of ERBB2 TMD/JMD
    mutants and EGFR
  findings: []
- id: Reactome:R-HSA-9670436
  title: p-KIT mutants:GRB2:SOS catalyzes nucleotide exchange on RAS
  findings: []
- id: Reactome:R-HSA-9672163
  title: SOS-mediated nucleotide exchange on RAS downstream of PDGFRA extracellular
    domain dimers
  findings: []
- id: Reactome:R-HSA-9672170
  title: SOS-mediated nucleotide exchange of RAS downstream of mutant PDGFR receptors
  findings: []
- id: Reactome:R-HSA-9695853
  title: FLT3 mutants:GRB2:SOS1-mediated nucleotide exchange on RAS
  findings: []
- id: Reactome:R-HSA-9703441
  title: SOS1-mediated nucleotide exchange of RAS downstream of FLT3 fusion mutants
  findings: []
- id: file:human/NRAS/NRAS-uniprot.txt
  title: UniProtKB P01111 (RASN_HUMAN) GTPase NRas record
  findings:
  - statement: NRAS binds GDP/GTP and possesses intrinsic GTPase activity (EC 3.6.5.2), cycling
      between GDP-bound inactive and GTP-bound active states under GEF/GAP control.
    supporting_text: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
  - statement: NRAS is a lipid-anchored peripheral membrane protein on the cytoplasmic side of
      the cell membrane and Golgi apparatus membrane, shuttling between the two.
    supporting_text: 'Note=Shuttles between the plasma membrane and the Golgi apparatus.'
  - statement: NRAS is farnesylated at Cys-186 and palmitoylated at Cys-181; palmitoylation by
      ZDHHC9-GOLGA7 and depalmitoylation by ABHD17A/B/C regulate PM-Golgi exchange.
    supporting_text: A continuous cycle of de- and re-palmitoylation regulates rapid exchange
      between plasma membrane and Golgi
  - statement: Oncogenic codon 12/13/61 mutations impair GTP hydrolysis and lock NRAS in the
      active GTP-bound state, transforming cells.
    supporting_text: Mutations which change AA 12, 13 or 61 activate the potential of Ras to
      transform cultured cells and are implicated in a variety of human tumors.
core_functions:
- description: NRAS is a membrane-anchored small GTPase that acts as a binary molecular switch,
    binding GDP/GTP and hydrolyzing GTP to GDP via its intrinsic GTPase activity.
  molecular_function:
    id: GO:0003924
    label: GTPase activity
  supported_by:
  - reference_id: file:human/NRAS/NRAS-uniprot.txt
    supporting_text: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
  - reference_id: PMID:30712867
    supporting_text: STK19 phosphorylates NRAS to enhance its binding to its downstream effectors
      and promotes oncogenic NRAS-mediated melanocyte malignant transformation.
- description: Active GTP-bound NRAS at the plasma membrane transduces receptor tyrosine kinase
    signals to downstream effectors, activating the RAF-MEK-ERK MAPK cascade.
  molecular_function:
    id: GO:0003924
    label: GTPase activity
  directly_involved_in:
  - id: GO:0007265
    label: Ras protein signal transduction
  - id: GO:0000165
    label: MAPK cascade
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0000139
    label: Golgi membrane
  supported_by:
  - reference_id: PMID:30712867
    supporting_text: STK19 phosphorylates NRAS to enhance its binding to its downstream effectors
      and promotes oncogenic NRAS-mediated melanocyte malignant transformation.
  - reference_id: PMID:18641128
    supporting_text: eNOS selectively activates N-Ras but not K-Ras on the Golgi complex of T
      cells engaged with APC.
- description: NRAS undergoes a de/re-palmitoylation acylation cycle that drives its shuttling
    between the plasma membrane and the Golgi apparatus, providing spatial control of signaling.
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0000139
    label: Golgi membrane
  supported_by:
  - reference_id: PMID:15705808
    supporting_text: driving their rapid exchange between the plasma membrane (PM) and the Golgi
      apparatus.
  - reference_id: PMID:26701913
    supporting_text: ABHD17 catalytic activity is required for N-Ras depalmitoylation and
      re-localization to internal cellular membranes.
proposed_new_terms: []
suggested_questions:
- question: To what extent are NRAS-specific (versus pan-RAS) downstream signaling outputs and
    effector preferences attributable to its hypervariable region and its distinctive
    palmitoylation/depalmitoylation-driven PM-Golgi trafficking?
  experts:
  - McCormick F
  - Bastiaens PIH
- question: Should NRAS receive a distinct molecular-function annotation for RAF/effector binding
    (e.g., a Ras-effector engagement term) given the many curated effector interactions currently
    captured only as generic protein binding?
  experts:
  - Thomas GV
suggested_experiments:
- hypothesis: NRAS effector engagement and signaling output are quantitatively shaped by its
    palmitoylation-dependent localization between plasma membrane and Golgi.
  description: Use acylation-cycle mutants (e.g., Cys181Ser) and ABHD17/ZDHHC9 perturbations
    combined with FRET-based Ras activity biosensors and phospho-ERK readouts to map how
    subcellular localization governs NRAS-driven MAPK activation.
  experiment_type: live-cell signaling and localization assay
- hypothesis: Ser-89 phosphorylation by STK19 selectively enhances oncogenic NRAS effector
    binding and MAPK output.
  description: Compare effector co-immunoprecipitation, GTP-loading, and downstream ERK
    activation for wild-type, S89A, and oncogenic (Q61R) NRAS in STK19-proficient versus
    STK19-deficient cells.
  experiment_type: biochemical effector-binding and phosphorylation assay