RASN_HUMAN
ID RASN_HUMAN Reviewed; 189 AA.
AC P01111; Q14971; Q15104; Q15282;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 03-AUG-2022, entry version 240.
DE RecName: Full=GTPase NRas;
DE EC=3.6.5.2 {ECO:0000250|UniProtKB:P01116};
DE AltName: Full=Transforming protein N-Ras;
DE Flags: Precursor;
GN Name=NRAS; Synonyms=HRAS1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6616621; DOI=10.1016/0092-8674(83)90390-2;
RA Taparowsky E., Shimizu K., Goldfarb M., Wigler M.;
RT "Structure and activation of the human N-ras gene.";
RL Cell 34:581-586(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2991860; DOI=10.1093/nar/13.14.5255;
RA Hall A., Brown R.;
RT "Human N-ras: cDNA cloning and gene structure.";
RL Nucleic Acids Res. 13:5255-5268(1985).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Fibrosarcoma;
RX PubMed=6086315; DOI=10.1002/j.1460-2075.1984.tb01970.x;
RA Brown R., Marshall C.J., Pennie S.G., Hall A.;
RT "Mechanism of activation of an N-ras gene in the human fibrosarcoma cell
RT line HT1080.";
RL EMBO J. 3:1321-1326(1984).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Lung carcinoma;
RX PubMed=6587382; DOI=10.1073/pnas.81.12.3670;
RA Yuasa Y., Gol R.A., Chang A., Chiu I.-M., Reddy E.P., Tronick S.R.,
RA Aaronson S.A.;
RT "Mechanism of activation of an N-ras oncogene of SW-1271 human lung
RT carcinoma cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:3670-3674(1984).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction sequenced by
RT the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE OF 1-96, AND VARIANT CYS-12.
RC TISSUE=Leukemia;
RX PubMed=2998510;
RA Hirai H., Tanaka S., Azuma M., Anraku Y., Kobayashi Y., Fujisawa M.,
RA Okabe T., Urabe A., Takaku F.;
RT "Transforming genes in human leukemia cells.";
RL Blood 66:1371-1378(1985).
RN [9]
RP NUCLEOTIDE SEQUENCE OF 1-29 AND 43-78.
RX PubMed=1970154;
RA Yuasa Y., Kamiyama T., Kato M., Iwama T., Ikeuchi T., Tonomura A.;
RT "Transforming genes from familial adenomatous polyposis patient cells
RT detected by a tumorigenicity assay.";
RL Oncogene 5:589-596(1990).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 38-96.
RX PubMed=3856237; DOI=10.1073/pnas.82.3.879;
RA Gambke C., Hall A., Moroni C.;
RT "Activation of an N-ras gene in acute myeloblastic leukemia through somatic
RT mutation in the first exon.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:879-882(1985).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 38-96.
RC TISSUE=Bone marrow;
RX PubMed=3295562; DOI=10.1038/327430a0;
RA Hirai H., Kobayashi Y., Mano H., Hagiwara K., Maru Y., Omine M.,
RA Mizoguchi H., Nishida J., Takaku F.;
RT "A point mutation at codon 13 of the N-ras oncogene in myelodysplastic
RT syndrome.";
RL Nature 327:430-432(1987).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 60-96, AND VARIANT ARG-61.
RX PubMed=3276402;
RA Raybaud F., Noguchi T., Marics I., Adelaide J., Planche J., Batoz M.,
RA Aubet C., de Lapeyriere O., Birnbaum D.;
RT "Detection of a low frequency of activated ras genes in human melanomas
RT using a tumorigenicity assay.";
RL Cancer Res. 48:950-953(1988).
RN [13]
RP PALMITOYLATION AT CYS-181, AND ISOPRENYLATION AT CYS-186.
RX PubMed=2661017; DOI=10.1016/0092-8674(89)90054-8;
RA Hancock J.F., Magee A.I., Childs J.E., Marshall C.J.;
RT "All ras proteins are polyisoprenylated but only some are palmitoylated.";
RL Cell 57:1167-1177(1989).
RN [14]
RP INVOLVEMENT IN NMTC2, AND VARIANT NMTC2 ARG-61.
RX PubMed=12727991; DOI=10.1210/jc.2002-021907;
RA Nikiforova M.N., Lynch R.A., Biddinger P.W., Alexander E.K., Dorn G.W. II,
RA Tallini G., Kroll T.G., Nikiforov Y.E.;
RT "RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors:
RT evidence for distinct molecular pathways in thyroid follicular carcinoma.";
RL J. Clin. Endocrinol. Metab. 88:2318-2326(2003).
RN [15]
RP PALMITOYLATION AT CYS-181.
RX PubMed=16000296; DOI=10.1074/jbc.m504113200;
RA Swarthout J.T., Lobo S., Farh L., Croke M.R., Greentree W.K.,
RA Deschenes R.J., Linder M.E.;
RT "DHHC9 and GCP16 constitute a human protein fatty acyltransferase with
RT specificity for H- and N-Ras.";
RL J. Biol. Chem. 280:31141-31148(2005).
RN [16]
RP PALMITOYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=15705808; DOI=10.1126/science.1105654;
RA Rocks O., Peyker A., Kahms M., Verveer P.J., Koerner C., Lumbierres M.,
RA Kuhlmann J., Waldmann H., Wittinghofer A., Bastiaens P.I.H.;
RT "An acylation cycle regulates localization and activity of palmitoylated
RT Ras isoforms.";
RL Science 307:1746-1752(2005).
RN [17]
RP GLYCOSYLATION AT THR-35 (MICROBIAL INFECTION).
RX PubMed=19744486; DOI=10.1016/j.febslet.2009.09.006;
RA Huelsenbeck S.C., Klose I., Reichenbach M., Huelsenbeck J., Genth H.;
RT "Distinct kinetics of (H/K/N)Ras glucosylation and Rac1 glucosylation
RT catalysed by Clostridium sordellii lethal toxin.";
RL FEBS Lett. 583:3133-3139(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP INTERACTION WITH RASSF7.
RX PubMed=21278800; DOI=10.1038/cdd.2010.137;
RA Takahashi S., Ebihara A., Kajiho H., Kontani K., Nishina H., Katada T.;
RT "RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the
RT activity of phosphorylated-MKK7.";
RL Cell Death Differ. 18:645-655(2011).
RN [20]
RP SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-181, AND MUTAGENESIS OF
RP CYS-181.
RX PubMed=26701913; DOI=10.7554/elife.11306;
RA Lin D.T., Conibear E.;
RT "ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras
RT palmitate turnover and subcellular localization.";
RL Elife 4:E11306-E11306(2015).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [22]
RP ACYLATION, AND MUTAGENESIS OF 169-LYS-LYS-170.
RX PubMed=29239724; DOI=10.7554/elife.32436;
RA Jing H., Zhang X., Wisner S.A., Chen X., Spiegelman N.A., Linder M.E.,
RA Lin H.;
RT "SIRT2 and lysine fatty acylation regulate the transforming activity of K-
RT Ras4a.";
RL Elife 6:0-0(2017).
RN [23]
RP UBIQUITINATION AT LYS-170.
RX PubMed=30442762; DOI=10.1126/science.aap7607;
RA Steklov M., Pandolfi S., Baietti M.F., Batiuk A., Carai P., Najm P.,
RA Zhang M., Jang H., Renzi F., Cai Y., Abbasi Asbagh L., Pastor T.,
RA De Troyer M., Simicek M., Radaelli E., Brems H., Legius E., Tavernier J.,
RA Gevaert K., Impens F., Messiaen L., Nussinov R., Heymans S., Eyckerman S.,
RA Sablina A.A.;
RT "Mutations in LZTR1 drive human disease by dysregulating RAS
RT ubiquitination.";
RL Science 362:1177-1182(2018).
RN [24]
RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-89, MUTAGENESIS OF
RP SER-89, VARIANT ARG-61, AND CHARACTERIZATION OF VARIANT ARG-61.
RX PubMed=30712867; DOI=10.1016/j.cell.2019.01.002;
RA Yin C., Zhu B., Zhang T., Liu T., Chen S., Liu Y., Li X., Miao X., Li S.,
RA Mi X., Zhang J., Li L., Wei G., Xu Z.X., Gao X., Huang C., Wei Z.,
RA Goding C.R., Wang P., Deng X., Cui R.;
RT "Pharmacological targeting of STK19 inhibits oncogenic NRAS-driven
RT melanomagenesis.";
RL Cell 176:1113-1127(2019).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 1-172 IN COMPLEX WITH GDP.
RA Nedyalkova L., Tong Y., Tempel W., Shen L., Loppnau P., Arrowsmith C.H.,
RA Edwards A.M., Bountra C., Weigelt J., Bochkarev A., Park H.;
RT "Crystal structure of the human NRAS GTPase bound with GDP.";
RL Submitted (MAR-2008) to the PDB data bank.
RN [26]
RP VARIANT COLORECTAL CANCER ARG-13.
RX PubMed=3102434;
RA Nitta N., Ochiai M., Nagao M., Sugimura T.;
RT "Amino-acid substitution at codon 13 of the N-ras oncogene in rectal cancer
RT in a Japanese patient.";
RL Jpn. J. Cancer Res. 78:21-26(1987).
RN [27]
RP VARIANTS JMML ASP-12 AND ASP-13.
RX PubMed=17332249; DOI=10.1182/blood-2006-09-046649;
RA Matsuda K., Shimada A., Yoshida N., Ogawa A., Watanabe A., Yajima S.,
RA Iizuka S., Koike K., Yanai F., Kawasaki K., Yanagimachi M., Kikuchi A.,
RA Ohtsuka Y., Hidaka E., Yamauchi K., Tanaka M., Yanagisawa R., Nakazawa Y.,
RA Shiohara M., Manabe A., Kojima S., Koike K.;
RT "Spontaneous improvement of hematologic abnormalities in patients having
RT juvenile myelomonocytic leukemia with specific RAS mutations.";
RL Blood 109:5477-5480(2007).
RN [28]
RP VARIANT RALD ASP-13.
RX PubMed=17517660; DOI=10.1073/pnas.0702975104;
RA Oliveira J.B., Bidere N., Niemela J.E., Zheng L., Sakai K., Nix C.P.,
RA Danner R.L., Barb J., Munson P.J., Puck J.M., Dale J., Straus S.E.,
RA Fleisher T.A., Lenardo M.J.;
RT "NRAS mutation causes a human autoimmune lymphoproliferative syndrome.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:8953-8958(2007).
RN [29]
RP VARIANTS CMNS ARG-13 AND ARG-61.
RX PubMed=18633438; DOI=10.1038/jid.2008.203;
RA Dessars B., De Raeve L.E., Morandini R., Lefort A., El Housni H.,
RA Ghanem G.E., Van den Eynde B.J., Ma W., Roseeuw D., Vassart G., Libert F.,
RA Heimann P.;
RT "Genotypic and gene expression studies in congenital melanocytic nevi:
RT insight into initial steps of melanotumorigenesis.";
RL J. Invest. Dermatol. 129:139-147(2009).
RN [30]
RP VARIANTS NS6 ILE-50 AND GLU-60, AND CHARACTERIZATION OF VARIANTS NS6 ILE-50
RP AND GLU-60.
RX PubMed=19966803; DOI=10.1038/ng.497;
RA Cirstea I.C., Kutsche K., Dvorsky R., Gremer L., Carta C., Horn D.,
RA Roberts A.E., Lepri F., Merbitz-Zahradnik T., Konig R., Kratz C.P.,
RA Pantaleoni F., Dentici M.L., Joshi V.A., Kucherlapati R.S., Mazzanti L.,
RA Mundlos S., Patton M.A., Silengo M.C., Rossi C., Zampino G., Digilio C.,
RA Stuppia L., Seemanova E., Pennacchio L.A., Gelb B.D., Dallapiccola B.,
RA Wittinghofer A., Ahmadian M.R., Tartaglia M., Zenker M.;
RT "A restricted spectrum of NRAS mutations causes Noonan syndrome.";
RL Nat. Genet. 42:27-29(2010).
RN [31]
RP VARIANTS KNEN ASP-12; LEU-34 AND ARG-61.
RX PubMed=22499344; DOI=10.1136/jmedgenet-2011-100637;
RA Hafner C., Toll A., Gantner S., Mauerer A., Lurkin I., Acquadro F.,
RA Fernandez-Casado A., Zwarthoff E.C., Dietmaier W., Baselga E., Parera E.,
RA Vicente A., Casanova A., Cigudosa J., Mentzel T., Pujol R.M.,
RA Landthaler M., Real F.X.;
RT "Keratinocytic epidermal nevi are associated with mosaic RAS mutations.";
RL J. Med. Genet. 49:249-253(2012).
RN [32]
RP VARIANTS CMNS ARG-61 AND LYS-61, AND VARIANTS NCMS ARG-61 AND LYS-61.
RX PubMed=23392294; DOI=10.1038/jid.2013.70;
RA Kinsler V.A., Thomas A.C., Ishida M., Bulstrode N.W., Loughlin S., Hing S.,
RA Chalker J., McKenzie K., Abu-Amero S., Slater O., Chanudet E., Palmer R.,
RA Morrogh D., Stanier P., Healy E., Sebire N.J., Moore G.E.;
RT "Multiple congenital melanocytic nevi and neurocutaneous melanosis are
RT caused by postzygotic mutations in codon 61 of NRAS.";
RL J. Invest. Dermatol. 133:2229-2236(2013).
CC -!- FUNCTION: Ras proteins bind GDP/GTP and possess intrinsic GTPase
CC activity. {ECO:0000269|PubMed:30712867}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; EC=3.6.5.2;
CC Evidence={ECO:0000250|UniProtKB:P01116};
CC -!- ACTIVITY REGULATION: Alternates between an inactive form bound to GDP
CC and an active form bound to GTP. Activated by a guanine nucleotide-
CC exchange factor (GEF) and inactivated by a GTPase-activating protein
CC (GAP).
CC -!- SUBUNIT: Interacts (active GTP-bound form preferentially) with RGS14
CC (By similarity). Interacts (active GTP-bound form) with RASSF7
CC (PubMed:21278800). {ECO:0000250|UniProtKB:Q04970,
CC ECO:0000269|PubMed:21278800}.
CC -!- INTERACTION:
CC P01111; Q96II5: ARAF; NbExp=3; IntAct=EBI-721993, EBI-9383168;
CC P01111; P15056: BRAF; NbExp=5; IntAct=EBI-721993, EBI-365980;
CC P01111; P27986-2: PIK3R1; NbExp=3; IntAct=EBI-721993, EBI-9090282;
CC P01111; P04049: RAF1; NbExp=9; IntAct=EBI-721993, EBI-365996;
CC P01111; P52306-5: RAP1GDS1; NbExp=6; IntAct=EBI-721993, EBI-12832744;
CC P01111; Q3MIN7: RGL3; NbExp=3; IntAct=EBI-721993, EBI-2856274;
CC P01111; Q13671: RIN1; NbExp=9; IntAct=EBI-721993, EBI-366017;
CC P01111; P28028: Braf; Xeno; NbExp=2; IntAct=EBI-721993, EBI-2584830;
CC P01111; Q99N57: Raf1; Xeno; NbExp=2; IntAct=EBI-721993, EBI-397757;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15705808,
CC ECO:0000269|PubMed:26701913}; Lipid-anchor
CC {ECO:0000269|PubMed:15705808, ECO:0000269|PubMed:26701913}; Cytoplasmic
CC side {ECO:0000269|PubMed:15705808, ECO:0000269|PubMed:26701913}. Golgi
CC apparatus membrane {ECO:0000269|PubMed:15705808,
CC ECO:0000269|PubMed:26701913}; Lipid-anchor
CC {ECO:0000269|PubMed:15705808, ECO:0000269|PubMed:26701913}.
CC Note=Shuttles between the plasma membrane and the Golgi apparatus.
CC {ECO:0000269|PubMed:15705808, ECO:0000269|PubMed:26701913}.
CC -!- PTM: Palmitoylated by the ZDHHC9-GOLGA7 complex (PubMed:16000296).
CC Depalmitoylated by ABHD17A, ABHD17B and ABHD17C (PubMed:26701913). A
CC continuous cycle of de- and re-palmitoylation regulates rapid exchange
CC between plasma membrane and Golgi (PubMed:16000296, PubMed:15705808,
CC PubMed:2661017, PubMed:26701913). {ECO:0000269|PubMed:15705808,
CC ECO:0000269|PubMed:16000296, ECO:0000269|PubMed:2661017,
CC ECO:0000269|PubMed:26701913}.
CC -!- PTM: Acetylation at Lys-104 prevents interaction with guanine
CC nucleotide exchange factors (GEFs). {ECO:0000250|UniProtKB:P01116}.
CC -!- PTM: Fatty-acylated at Lys-169 and/or Lys-170.
CC {ECO:0000269|PubMed:29239724}.
CC -!- PTM: Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at
CC Lys-170 in a non-degradative manner, leading to inhibit Ras signaling
CC by decreasing Ras association with membranes.
CC {ECO:0000305|PubMed:30442762}.
CC -!- PTM: Phosphorylation at Ser-89 by STK19 enhances NRAS-association with
CC its downstream effectors. {ECO:0000269|PubMed:30712867}.
CC -!- PTM: (Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin
CC TcsL. {ECO:0000269|PubMed:19744486}.
CC -!- DISEASE: Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An
CC aggressive pediatric myelodysplastic syndrome/myeloproliferative
CC disorder characterized by malignant transformation in the hematopoietic
CC stem cell compartment with proliferation of differentiated progeny.
CC Patients have splenomegaly, enlarged lymph nodes, rashes, and
CC hemorrhages. {ECO:0000269|PubMed:17332249}. Note=The disease is caused
CC by variants affecting the gene represented in this entry.
CC -!- DISEASE: Noonan syndrome 6 (NS6) [MIM:613224]: A form of Noonan
CC syndrome, a disease characterized by short stature, facial dysmorphic
CC features such as hypertelorism, a downward eyeslant and low-set
CC posteriorly rotated ears, and a high incidence of congenital heart
CC defects and hypertrophic cardiomyopathy. Other features can include a
CC short neck with webbing or redundancy of skin, deafness, motor delay,
CC variable intellectual deficits, multiple skeletal defects,
CC cryptorchidism, and bleeding diathesis. Individuals with Noonan
CC syndrome are at risk of juvenile myelomonocytic leukemia, a
CC myeloproliferative disorder characterized by excessive production of
CC myelomonocytic cells. {ECO:0000269|PubMed:19966803}. Note=The disease
CC is caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: RAS-associated autoimmune leukoproliferative disorder (RALD)
CC [MIM:614470]: A disorder of apoptosis, characterized by chronic
CC accumulation of non-malignant lymphocytes, defective lymphocyte
CC apoptosis, and an increased risk for the development of hematologic
CC malignancies. {ECO:0000269|PubMed:17517660}. Note=The disease is caused
CC by variants affecting the gene represented in this entry.
CC -!- DISEASE: Melanocytic nevus syndrome, congenital (CMNS) [MIM:137550]: A
CC syndrome characterized by congenital pigmentary skin lesions which can
CC occur at any site and can cover most of the body surface. These lesions
CC may or may not be hairy. Congenital melanocytic nevi are associated
CC with neuromelanosis (the presence of melanin-producing cells within the
CC brain parenchyma or leptomeninges). Less commonly they are associated
CC with malignant melanoma in childhood, both in the skin and the central
CC nervous system. CMNS patients also tend to have a characteristic facial
CC appearance, including wide or prominent forehead, periorbital fullness,
CC small short nose with narrow nasal bridge, round face, full cheeks,
CC prominent premaxilla, and everted lower lip.
CC {ECO:0000269|PubMed:18633438, ECO:0000269|PubMed:23392294}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Melanosis, neurocutaneous (NCMS) [MIM:249400]: A rare
CC congenital disease characterized by the presence of giant or multiple
CC melanocytic nevi on the skin, foci of melanin-producing cells within
CC the brain parenchyma, and infiltration of leptomeninges by abnormal
CC melanin deposits. Neurologic abnormalities include seizures,
CC hydrocephalus, arachnoid cysts, tumors, and syringomyelia. Some
CC patients may develop malignant melanoma. {ECO:0000269|PubMed:23392294}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900]:
CC Epidermal nevi of the common, non-organoid and non-epidermolytic type
CC are benign skin lesions and may vary in their extent from a single
CC (usually linear) lesion to widespread and systematized involvement.
CC They may be present at birth or develop early during childhood.
CC {ECO:0000269|PubMed:22499344}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Thyroid cancer, non-medullary, 2 (NMTC2) [MIM:188470]: A form
CC of non-medullary thyroid cancer (NMTC), a cancer characterized by
CC tumors originating from the thyroid follicular cells. NMTCs represent
CC approximately 95% of all cases of thyroid cancer and are classified
CC into papillary, follicular, Hurthle cell, and anaplastic neoplasms.
CC {ECO:0000269|PubMed:12727991}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Mutations which change AA 12, 13 or 61 activate the
CC potential of Ras to transform cultured cells and are implicated in a
CC variety of human tumors.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/NRASID92.html";
CC -!- WEB RESOURCE: Name=NRASbase; Note=NRAS mutation db;
CC URL="http://structure.bmc.lu.se/idbase/NRASbase/";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/nras/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=RAS proteins entry;
CC URL="https://en.wikipedia.org/wiki/RAS_proteins";
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DR EMBL; X02751; CAA26529.1; -; mRNA.
DR EMBL; X00642; CAA25269.1; -; Genomic_DNA.
DR EMBL; X00643; CAA25270.1; -; Genomic_DNA.
DR EMBL; X00644; CAA25271.1; -; Genomic_DNA.
DR EMBL; X00645; CAA25272.1; -; Genomic_DNA.
DR EMBL; L00043; AAA60255.1; -; Genomic_DNA.
DR EMBL; L00040; AAA60255.1; JOINED; Genomic_DNA.
DR EMBL; L00041; AAA60255.1; JOINED; Genomic_DNA.
DR EMBL; L00042; AAA60255.1; JOINED; Genomic_DNA.
DR EMBL; AF493919; AAM12633.1; -; mRNA.
DR EMBL; AY428630; AAQ94397.1; -; Genomic_DNA.
DR EMBL; BC005219; AAH05219.1; -; mRNA.
DR EMBL; M25898; AAA36548.1; -; Genomic_DNA.
DR EMBL; X53291; CAA37384.1; -; Genomic_DNA.
DR EMBL; X53292; CAA37384.1; JOINED; Genomic_DNA.
DR EMBL; K03211; AAA36556.1; -; Genomic_DNA.
DR EMBL; M10055; AAA36556.1; JOINED; Genomic_DNA.
DR EMBL; X05565; CAA29079.1; -; Genomic_DNA.
DR EMBL; X07440; CAA30320.1; -; Genomic_DNA.
DR CCDS; CCDS877.1; -.
DR PIR; A90839; TVHURA.
DR PIR; I38149; I38149.
DR RefSeq; NP_002515.1; NM_002524.4.
DR PDB; 2N9C; NMR; -; A=1-17.
DR PDB; 3CON; X-ray; 1.65 A; A=1-172.
DR PDB; 5UHV; X-ray; 1.67 A; A=1-166.
DR PDB; 6E6H; X-ray; 1.99 A; A=1-166.
DR PDB; 6MPP; NMR; -; B=55-64.
DR PDB; 6ULI; X-ray; 1.88 A; C=10-18.
DR PDB; 6ULK; X-ray; 1.90 A; C=10-19.
DR PDB; 6ULN; X-ray; 2.01 A; C=10-18.
DR PDB; 6ULR; X-ray; 3.20 A; C=10-18.
DR PDB; 6UON; X-ray; 3.50 A; C/F=10-19.
DR PDB; 6WGH; X-ray; 1.65 A; A/B=1-170.
DR PDB; 6ZIO; X-ray; 1.55 A; A/B=1-172.
DR PDB; 6ZIR; X-ray; 1.90 A; A=1-172.
DR PDB; 6ZIZ; X-ray; 1.78 A; A/B=1-172.
DR PDBsum; 2N9C; -.
DR PDBsum; 3CON; -.
DR PDBsum; 5UHV; -.
DR PDBsum; 6E6H; -.
DR PDBsum; 6MPP; -.
DR PDBsum; 6ULI; -.
DR PDBsum; 6ULK; -.
DR PDBsum; 6ULN; -.
DR PDBsum; 6ULR; -.
DR PDBsum; 6UON; -.
DR PDBsum; 6WGH; -.
DR PDBsum; 6ZIO; -.
DR PDBsum; 6ZIR; -.
DR PDBsum; 6ZIZ; -.
DR AlphaFoldDB; P01111; -.
DR SMR; P01111; -.
DR BioGRID; 110952; 678.
DR DIP; DIP-1058N; -.
DR ELM; P01111; -.
DR IntAct; P01111; 521.
DR MINT; P01111; -.
DR STRING; 9606.ENSP00000358548; -.
DR BindingDB; P01111; -.
DR ChEMBL; CHEMBL2079845; -.
DR GuidetoPHARMACOLOGY; 2823; -.
DR GlyGen; P01111; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P01111; -.
DR MetOSite; P01111; -.
DR PhosphoSitePlus; P01111; -.
DR SwissPalm; P01111; -.
DR BioMuta; NRAS; -.
DR DMDM; 131883; -.
DR OGP; P01111; -.
DR CPTAC; CPTAC-1549; -.
DR EPD; P01111; -.
DR jPOST; P01111; -.
DR MassIVE; P01111; -.
DR PaxDb; P01111; -.
DR PeptideAtlas; P01111; -.
DR PRIDE; P01111; -.
DR ProteomicsDB; 51320; -.
DR ABCD; P01111; 1 sequenced antibody.
DR Antibodypedia; 4118; 589 antibodies from 41 providers.
DR DNASU; 4893; -.
DR Ensembl; ENST00000369535.5; ENSP00000358548.4; ENSG00000213281.5.
DR GeneID; 4893; -.
DR KEGG; hsa:4893; -.
DR MANE-Select; ENST00000369535.5; ENSP00000358548.4; NM_002524.5; NP_002515.1.
DR CTD; 4893; -.
DR DisGeNET; 4893; -.
DR GeneCards; NRAS; -.
DR GeneReviews; NRAS; -.
DR HGNC; HGNC:7989; NRAS.
DR HPA; ENSG00000213281; Low tissue specificity.
DR MalaCards; NRAS; -.
DR MIM; 137550; phenotype.
DR MIM; 162900; phenotype.
DR MIM; 164790; gene.
DR MIM; 188470; phenotype.
DR MIM; 249400; phenotype.
DR MIM; 607785; phenotype.
DR MIM; 613224; phenotype.
DR MIM; 614470; phenotype.
DR neXtProt; NX_P01111; -.
DR OpenTargets; ENSG00000213281; -.
DR Orphanet; 146; Differentiated thyroid carcinoma.
DR Orphanet; 86834; Juvenile myelomonocytic leukemia.
DR Orphanet; 389; Langerhans cell histiocytosis.
DR Orphanet; 626; Large congenital melanocytic nevus.
DR Orphanet; 2612; Linear nevus sebaceus syndrome.
DR Orphanet; 411533; NON RARE IN EUROPE: Melanoma.
DR Orphanet; 648; Noonan syndrome.
DR Orphanet; 268114; RAS-associated autoimmune leukoproliferative disease.
DR Orphanet; 357194; Selection of therapeutic option in colorectal cancer.
DR Orphanet; 544260; Selection of therapeutic option in melanoma.
DR PharmGKB; PA31768; -.
DR VEuPathDB; HostDB:ENSG00000213281; -.
DR eggNOG; KOG0395; Eukaryota.
DR GeneTree; ENSGT00940000158947; -.
DR HOGENOM; CLU_041217_9_8_1; -.
DR InParanoid; P01111; -.
DR OMA; QGCMGVS; -.
DR OrthoDB; 1259506at2759; -.
DR PhylomeDB; P01111; -.
DR TreeFam; TF312796; -.
DR PathwayCommons; P01111; -.
DR Reactome; R-HSA-112412; SOS-mediated signalling.
DR Reactome; R-HSA-1169092; Activation of RAS in B cells.
DR Reactome; R-HSA-1236382; Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants.
DR Reactome; R-HSA-1250196; SHC1 events in ERBB2 signaling.
DR Reactome; R-HSA-1250347; SHC1 events in ERBB4 signaling.
DR Reactome; R-HSA-1433557; Signaling by SCF-KIT.
DR Reactome; R-HSA-167044; Signalling to RAS.
DR Reactome; R-HSA-171007; p38MAPK events.
DR Reactome; R-HSA-179812; GRB2 events in EGFR signaling.
DR Reactome; R-HSA-180336; SHC1 events in EGFR signaling.
DR Reactome; R-HSA-186763; Downstream signal transduction.
DR Reactome; R-HSA-1963640; GRB2 events in ERBB2 signaling.
DR Reactome; R-HSA-210993; Tie2 Signaling.
DR Reactome; R-HSA-2179392; EGFR Transactivation by Gastrin.
DR Reactome; R-HSA-2424491; DAP12 signaling.
DR Reactome; R-HSA-2428933; SHC-related events triggered by IGF1R.
DR Reactome; R-HSA-2871796; FCERI mediated MAPK activation.
DR Reactome; R-HSA-375165; NCAM signaling for neurite out-growth.
DR Reactome; R-HSA-442982; Ras activation upon Ca2+ influx through NMDA receptor.
DR Reactome; R-HSA-5218921; VEGFR2 mediated cell proliferation.
DR Reactome; R-HSA-5621575; CD209 (DC-SIGN) signaling.
DR Reactome; R-HSA-5637810; Constitutive Signaling by EGFRvIII.
DR Reactome; R-HSA-5654688; SHC-mediated cascade:FGFR1.
DR Reactome; R-HSA-5654693; FRS-mediated FGFR1 signaling.
DR Reactome; R-HSA-5654699; SHC-mediated cascade:FGFR2.
DR Reactome; R-HSA-5654700; FRS-mediated FGFR2 signaling.
DR Reactome; R-HSA-5654704; SHC-mediated cascade:FGFR3.
DR Reactome; R-HSA-5654706; FRS-mediated FGFR3 signaling.
DR Reactome; R-HSA-5654712; FRS-mediated FGFR4 signaling.
DR Reactome; R-HSA-5654719; SHC-mediated cascade:FGFR4.
DR Reactome; R-HSA-5655253; Signaling by FGFR2 in disease.
DR Reactome; R-HSA-5655291; Signaling by FGFR4 in disease.
DR Reactome; R-HSA-5655302; Signaling by FGFR1 in disease.
DR Reactome; R-HSA-5655332; Signaling by FGFR3 in disease.
DR Reactome; R-HSA-5658442; Regulation of RAS by GAPs.
DR Reactome; R-HSA-5673000; RAF activation.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-5674135; MAP2K and MAPK activation.
DR Reactome; R-HSA-5675221; Negative regulation of MAPK pathway.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR Reactome; R-HSA-6802946; Signaling by moderate kinase activity BRAF mutants.
DR Reactome; R-HSA-6802948; Signaling by high-kinase activity BRAF mutants.
DR Reactome; R-HSA-6802952; Signaling by BRAF and RAF1 fusions.
DR Reactome; R-HSA-6802953; RAS signaling downstream of NF1 loss-of-function variants.
DR Reactome; R-HSA-6802955; Paradoxical activation of RAF signaling by kinase inactive BRAF.
DR Reactome; R-HSA-74751; Insulin receptor signalling cascade.
DR Reactome; R-HSA-8849471; PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases.
DR Reactome; R-HSA-8851805; MET activates RAS signaling.
DR Reactome; R-HSA-9026519; Activated NTRK2 signals through RAS.
DR Reactome; R-HSA-9027284; Erythropoietin activates RAS.
DR Reactome; R-HSA-9028731; Activated NTRK2 signals through FRS2 and FRS3.
DR Reactome; R-HSA-9034864; Activated NTRK3 signals through RAS.
DR Reactome; R-HSA-9607240; FLT3 Signaling.
DR Reactome; R-HSA-9634285; Constitutive Signaling by Overexpressed ERBB2.
DR Reactome; R-HSA-9634635; Estrogen-stimulated signaling through PRKCZ.
DR Reactome; R-HSA-9648002; RAS processing.
DR Reactome; R-HSA-9649948; Signaling downstream of RAS mutants.
DR Reactome; R-HSA-9656223; Signaling by RAF1 mutants.
DR Reactome; R-HSA-9664565; Signaling by ERBB2 KD Mutants.
DR Reactome; R-HSA-9665348; Signaling by ERBB2 ECD mutants.
DR Reactome; R-HSA-9665686; Signaling by ERBB2 TMD/JMD mutants.
DR Reactome; R-HSA-9670439; Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants.
DR Reactome; R-HSA-9673767; Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants.
DR Reactome; R-HSA-9673770; Signaling by PDGFRA extracellular domain mutants.
DR Reactome; R-HSA-9703465; Signaling by FLT3 fusion proteins.
DR Reactome; R-HSA-9703648; Signaling by FLT3 ITD and TKD mutants.
DR Reactome; R-HSA-9753510; Signaling by RAS GAP mutants.
DR Reactome; R-HSA-9753512; Signaling by RAS GTPase mutants.
DR SignaLink; P01111; -.
DR SIGNOR; P01111; -.
DR BioGRID-ORCS; 4893; 74 hits in 1082 CRISPR screens.
DR ChiTaRS; NRAS; human.
DR EvolutionaryTrace; P01111; -.
DR GeneWiki; Neuroblastoma_RAS_viral_oncogene_homolog; -.
DR GenomeRNAi; 4893; -.
DR Pharos; P01111; Tchem.
DR PRO; PR:P01111; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P01111; protein.
DR Bgee; ENSG00000213281; Expressed in gingival epithelium and 192 other tissues.
DR ExpressionAtlas; P01111; baseline and differential.
DR Genevisible; P01111; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:CACAO.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0070821; C:tertiary granule membrane; TAS:Reactome.
DR GO; GO:0003925; F:G protein activity; IEA:UniProtKB-EC.
DR GO; GO:0019003; F:GDP binding; IBA:GO_Central.
DR GO; GO:0005525; F:GTP binding; IBA:GO_Central.
DR GO; GO:0003924; F:GTPase activity; IDA:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:MGI.
DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IMP:BHF-UCL.
DR GO; GO:0007265; P:Ras protein signal transduction; IDA:UniProtKB.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR020849; Small_GTPase_Ras-type.
DR PANTHER; PTHR24070; PTHR24070; 1.
DR Pfam; PF00071; Ras; 1.
DR SMART; SM00174; RHO; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51421; RAS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell membrane; Disease variant; Glycoprotein;
KW Golgi apparatus; GTP-binding; Hydrolase; Isopeptide bond; Lipoprotein;
KW Membrane; Methylation; Nucleotide-binding; Palmitate; Phosphoprotein;
KW Prenylation; Proto-oncogene; Reference proteome; Ubl conjugation.
FT CHAIN 1..186
FT /note="GTPase NRas"
FT /id="PRO_0000043006"
FT PROPEP 187..189
FT /note="Removed in mature form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000043007"
FT REGION 166..185
FT /note="Hypervariable region"
FT MOTIF 32..40
FT /note="Effector region"
FT BINDING 10..18
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|Ref.25"
FT BINDING 29..30
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|Ref.25"
FT BINDING 57..61
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000255"
FT BINDING 116..119
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|Ref.25"
FT MOD_RES 89
FT /note="Phosphoserine; by STK19"
FT /evidence="ECO:0000269|PubMed:30712867"
FT LIPID 181
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:16000296,
FT ECO:0000269|PubMed:2661017, ECO:0000269|PubMed:26701913"
FT LIPID 186
FT /note="S-farnesyl cysteine"
FT /evidence="ECO:0000269|PubMed:2661017"
FT CARBOHYD 35
FT /note="(Microbial infection) O-linked (Glc) threonine; by
FT P.sordellii toxin TcsL"
FT /evidence="ECO:0000269|PubMed:19744486"
FT CROSSLNK 170
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000305|PubMed:30442762"
FT VARIANT 12
FT /note="G -> C (in leukemia; dbSNP:rs121913250)"
FT /evidence="ECO:0000269|PubMed:2998510"
FT /id="VAR_021194"
FT VARIANT 12
FT /note="G -> D (in KNEN and JMML; dbSNP:rs121913237)"
FT /evidence="ECO:0000269|PubMed:17332249,
FT ECO:0000269|PubMed:22499344"
FT /id="VAR_071129"
FT VARIANT 13
FT /note="G -> D (in RALD and JMML; dbSNP:rs121434596)"
FT /evidence="ECO:0000269|PubMed:17332249,
FT ECO:0000269|PubMed:17517660"
FT /id="VAR_063084"
FT VARIANT 13
FT /note="G -> R (in CMNS and colorectal cancer; somatic
FT mutation; dbSNP:rs121434595)"
FT /evidence="ECO:0000269|PubMed:18633438,
FT ECO:0000269|PubMed:3102434"
FT /id="VAR_006845"
FT VARIANT 34
FT /note="P -> L (in KNEN; dbSNP:rs397514553)"
FT /evidence="ECO:0000269|PubMed:22499344"
FT /id="VAR_071130"
FT VARIANT 50
FT /note="T -> I (in NS6; hypermorphic mutation;
FT dbSNP:rs267606921)"
FT /evidence="ECO:0000269|PubMed:19966803"
FT /id="VAR_063085"
FT VARIANT 60
FT /note="G -> E (in NS6; hypermorphic mutation;
FT dbSNP:rs267606920)"
FT /evidence="ECO:0000269|PubMed:19966803"
FT /id="VAR_063086"
FT VARIANT 61
FT /note="Q -> K (in CMNS and NCMS; somatic mutation;
FT dbSNP:rs121913254)"
FT /evidence="ECO:0000269|PubMed:23392294"
FT /id="VAR_006846"
FT VARIANT 61
FT /note="Q -> R (in CMNS, NCMS, KNEN and NMTC2; also found in
FT lung carcinoma cell and melanoma; impaired GTP hydrolysis
FT activity, trapping NRAS in a constitutive GTP-bound active
FT conformation; promotes melanomagenesis; dbSNP:rs11554290)"
FT /evidence="ECO:0000269|PubMed:12727991,
FT ECO:0000269|PubMed:18633438, ECO:0000269|PubMed:22499344,
FT ECO:0000269|PubMed:23392294, ECO:0000269|PubMed:30712867,
FT ECO:0000269|PubMed:3276402"
FT /id="VAR_006847"
FT MUTAGEN 89
FT /note="S->A: Abolished phosphorylation by STK19."
FT /evidence="ECO:0000269|PubMed:30712867"
FT MUTAGEN 164
FT /note="R->A: Loss of GTP-binding activity."
FT MUTAGEN 169..170
FT /note="KK->RR: In N-Ras-2KR mutant; decreased fatty-
FT acylation."
FT /evidence="ECO:0000269|PubMed:29239724"
FT MUTAGEN 181
FT /note="C->S: Loss of plasma membrane localization."
FT /evidence="ECO:0000269|PubMed:26701913"
FT STRAND 2..9
FT /evidence="ECO:0007829|PDB:6ZIO"
FT HELIX 16..25
FT /evidence="ECO:0007829|PDB:6ZIO"
FT STRAND 38..46
FT /evidence="ECO:0007829|PDB:6ZIO"
FT STRAND 49..57
FT /evidence="ECO:0007829|PDB:6ZIO"
FT HELIX 62..64
FT /evidence="ECO:0007829|PDB:5UHV"
FT HELIX 66..74
FT /evidence="ECO:0007829|PDB:6ZIO"
FT STRAND 76..83
FT /evidence="ECO:0007829|PDB:6ZIO"
FT HELIX 87..104
FT /evidence="ECO:0007829|PDB:6ZIO"
FT STRAND 111..116
FT /evidence="ECO:0007829|PDB:6ZIO"
FT HELIX 127..137
FT /evidence="ECO:0007829|PDB:6ZIO"
FT STRAND 141..143
FT /evidence="ECO:0007829|PDB:6ZIO"
FT TURN 146..148
FT /evidence="ECO:0007829|PDB:6ZIO"
FT HELIX 152..166
FT /evidence="ECO:0007829|PDB:6ZIO"
SQ SEQUENCE 189 AA; 21229 MW; 6898D3F6815B1EC7 CRC64;
MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG
QEEYSAMRDQ YMRTGEGFLC VFAINNSKSF ADINLYREQI KRVKDSDDVP MVLVGNKCDL
PTRTVDTKQA HELAKSYGIP FIETSAKTRQ GVEDAFYTLV REIRQYRMKK LNSSDDGTQG
CMGLPCVVM
