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P35568

- IRS1_HUMAN

UniProt

P35568 - IRS1_HUMAN

Protein

Insulin receptor substrate 1

Gene

IRS1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 162 (01 Oct 2014)
      Sequence version 1 (01 Jun 1994)
      Previous versions | rss
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    Functioni

    May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit By similarity.By similarity

    GO - Molecular functioni

    1. insulin-like growth factor receptor binding Source: UniProtKB
    2. insulin receptor binding Source: UniProtKB
    3. phosphatidylinositol 3-kinase binding Source: UniProtKB
    4. protein binding Source: UniProtKB
    5. protein kinase C binding Source: BHF-UCL
    6. SH2 domain binding Source: UniProtKB
    7. signal transducer activity Source: ProtInc
    8. transmembrane receptor protein tyrosine kinase adaptor activity Source: BHF-UCL

    GO - Biological processi

    1. cellular response to insulin stimulus Source: BHF-UCL
    2. epidermal growth factor receptor signaling pathway Source: Reactome
    3. Fc-epsilon receptor signaling pathway Source: Reactome
    4. fibroblast growth factor receptor signaling pathway Source: Reactome
    5. glucose homeostasis Source: BHF-UCL
    6. innate immune response Source: Reactome
    7. insulin-like growth factor receptor signaling pathway Source: UniProtKB
    8. insulin receptor signaling pathway Source: UniProtKB
    9. JAK-STAT cascade involved in growth hormone signaling pathway Source: Reactome
    10. lipid catabolic process Source: Ensembl
    11. mammary gland development Source: Ensembl
    12. negative regulation of insulin receptor signaling pathway Source: BHF-UCL
    13. negative regulation of insulin secretion Source: BHF-UCL
    14. neurotrophin TRK receptor signaling pathway Source: Reactome
    15. phosphatidylinositol 3-kinase signaling Source: BHF-UCL
    16. phosphatidylinositol-mediated signaling Source: Reactome
    17. positive regulation of cell migration Source: Ensembl
    18. positive regulation of cell proliferation Source: BHF-UCL
    19. positive regulation of fatty acid beta-oxidation Source: BHF-UCL
    20. positive regulation of glucose import Source: BHF-UCL
    21. positive regulation of glucose import in response to insulin stimulus Source: BHF-UCL
    22. positive regulation of glucose metabolic process Source: BHF-UCL
    23. positive regulation of glycogen biosynthetic process Source: BHF-UCL
    24. positive regulation of insulin receptor signaling pathway Source: BHF-UCL
    25. positive regulation of mesenchymal cell proliferation Source: Ensembl
    26. positive regulation of phosphatidylinositol 3-kinase activity Source: BHF-UCL
    27. protein kinase B signaling Source: Ensembl
    28. protein localization to nucleus Source: Ensembl
    29. regulation of gene expression Source: Ensembl
    30. response to insulin Source: BHF-UCL
    31. response to peptide hormone Source: BHF-UCL
    32. signal transduction Source: ProtInc

    Keywords - Molecular functioni

    Transducer

    Enzyme and pathway databases

    ReactomeiREACT_111133. Growth hormone receptor signaling.
    REACT_12464. PI3K/AKT activation.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_150203. IRS-related events triggered by IGF1R.
    REACT_169118. Signaling by Leptin.
    REACT_508. Signal attenuation.
    REACT_524. SOS-mediated signalling.
    REACT_570. IRS activation.
    REACT_75829. PIP3 activates AKT signaling.
    REACT_976. PI3K Cascade.
    SignaLinkiP35568.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Insulin receptor substrate 1
    Short name:
    IRS-1
    Gene namesi
    Name:IRS1
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 2

    Organism-specific databases

    HGNCiHGNC:6125. IRS1.

    Subcellular locationi

    GO - Cellular componenti

    1. caveola Source: BHF-UCL
    2. cytoplasm Source: UniProtKB
    3. cytosol Source: Reactome
    4. insulin receptor complex Source: BHF-UCL
    5. intracellular membrane-bounded organelle Source: UniProtKB
    6. nucleus Source: UniProtKB
    7. plasma membrane Source: Reactome

    Pathology & Biotechi

    Involvement in diseasei

    Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.3 Publications
    Note: The gene represented in this entry may be involved in disease pathogenesis.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti723 – 7231Missing in NIDDM. 1 Publication
    VAR_005301
    Natural varianti1043 – 10431S → Y in NIDDM. 1 Publication
    VAR_005302
    Natural varianti1095 – 10951C → Y in NIDDM. 1 Publication
    VAR_005303

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi307 – 3071S → A: Impaired degradation by the Cul7-RING(FBXW8) complex; when associated with A-312; A-527; A-636 and A-639. 1 Publication
    Mutagenesisi312 – 3121S → A: Impaired degradation by the Cul7-RING(FBXW8) complex; when associated with A-307; A-527; A-636 and A-639. 1 Publication
    Mutagenesisi527 – 5271S → A: Impaired degradation by the Cul7-RING(FBXW8) complex; when associated with A-307; A-312; A-636 and A-639. 1 Publication
    Mutagenesisi636 – 6361S → A: Impaired degradation by the Cul7-RING(FBXW8) complex; when associated with A-307; A-312; A-527 and A-639. 1 Publication
    Mutagenesisi639 – 6391S → A: Impaired degradation by the Cul7-RING(FBXW8) complex; when associated with A-307; A-312; A-527 and A-636. 1 Publication
    Mutagenesisi794 – 7941S → A: Loss of phosphorylation by SIK2. 1 Publication

    Keywords - Diseasei

    Diabetes mellitus, Disease mutation

    Organism-specific databases

    MIMi125853. phenotype.
    PharmGKBiPA203.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 12421242Insulin receptor substrate 1PRO_0000084236Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei99 – 991Phosphoserine; by CK2By similarity
    Modified residuei270 – 2701Phosphoserine; by RPS6KB12 Publications
    Modified residuei307 – 3071Phosphoserine; by RPS6KB13 Publications
    Modified residuei312 – 3121Phosphoserine; by IKKB, MAPK8 and RPS6KB13 Publications
    Modified residuei345 – 3451PhosphoserineBy similarity
    Modified residuei348 – 3481Phosphoserine2 Publications
    Modified residuei465 – 4651Phosphotyrosine; by INSRBy similarity
    Modified residuei527 – 5271Phosphoserine; by RPS6KB12 Publications
    Modified residuei612 – 6121Phosphotyrosine; by INSR1 Publication
    Modified residuei629 – 6291Phosphoserine2 Publications
    Modified residuei632 – 6321Phosphotyrosine; by INSR1 Publication
    Modified residuei636 – 6361Phosphoserine; by RPS6KB14 Publications
    Modified residuei662 – 6621Phosphotyrosine2 Publications
    Modified residuei794 – 7941Phosphoserine; by AMPK and SIK22 Publications
    Modified residuei896 – 8961Phosphotyrosine; by INSRBy similarity
    Modified residuei941 – 9411Phosphotyrosine; by INSR2 Publications
    Modified residuei989 – 9891Phosphotyrosine; by INSRBy similarity
    Modified residuei1101 – 11011Phosphoserine; by RPS6KB1 and PKC/PRKCQ3 Publications
    Modified residuei1179 – 11791Phosphotyrosine; by INSRBy similarity
    Modified residuei1229 – 12291Phosphotyrosine; by INSRBy similarity

    Post-translational modificationi

    Serine phosphorylation of IRS1 is a mechanism for insulin resistance. Ser-312 phosphorylation inhibits insulin action through disruption of IRS1 interaction with the insulin receptor By similarity. Phosphorylation of Tyr-896 is required for GRB2-binding By similarity. Phosphorylated by ALK. Phosphorylated at Ser-270, Ser-307, Ser-636 and Ser-1101 by RPS6KB1; phosphorylation induces accelerated degradation of IRS1.By similarity5 Publications
    Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-dependent manner, leading to its degradation: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2).1 Publication

    Keywords - PTMi

    Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiP35568.
    PaxDbiP35568.
    PRIDEiP35568.

    PTM databases

    PhosphoSiteiP35568.

    Miscellaneous databases

    PMAP-CutDBP35568.

    Expressioni

    Gene expression databases

    BgeeiP35568.
    CleanExiHS_IRS1.
    GenevestigatoriP35568.

    Organism-specific databases

    HPAiCAB005261.
    HPA046433.
    HPA050221.

    Interactioni

    Subunit structurei

    Interacts with UBTF and PIK3CA By similarity. Interacts (via phosphorylated YXXM motifs) with PIK3R1 By similarity. Interacts with ROCK1 and FER By similarity. Interacts (via PH domain) with PHIP By similarity. Interacts with GRB2 By similarity. Interacts with SOCS7. Interacts (via IRS-type PTB domain) with IGF1R and INSR (via the tyrosine-phosphorylated NPXY motif). Interacts with ALK. Interacts with EIF2AK2/PKR By similarity.By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    P030702EBI-517592,EBI-617698From a different organism.
    ERBB2P046262EBI-517592,EBI-641062
    INSRP062133EBI-517592,EBI-475899
    NSP034952EBI-517592,EBI-2548993From a different organism.
    PABPC1P119402EBI-517592,EBI-81531
    PIK3CAP4233620EBI-517592,EBI-2116585
    PIK3R1P2798612EBI-517592,EBI-79464
    PTPN11Q061243EBI-517592,EBI-297779

    Protein-protein interaction databases

    BioGridi109874. 59 interactions.
    DIPiDIP-523N.
    IntActiP35568. 20 interactions.
    MINTiMINT-149537.
    STRINGi9606.ENSP00000304895.

    Structurei

    Secondary structure

    1
    1242
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi13 – 208
    Turni22 – 243
    Beta strandi27 – 337
    Turni37 – 393
    Beta strandi40 – 4910
    Helixi50 – 545
    Beta strandi61 – 655
    Helixi66 – 683
    Beta strandi69 – 757
    Beta strandi81 – 9010
    Beta strandi92 – 965
    Helixi100 – 11314
    Beta strandi161 – 17212
    Helixi173 – 1764
    Beta strandi181 – 1877
    Beta strandi189 – 1968
    Beta strandi203 – 2075
    Helixi208 – 2103
    Beta strandi211 – 2177
    Beta strandi220 – 2256
    Beta strandi233 – 2397
    Helixi243 – 25816
    Helixi259 – 2613
    Beta strandi897 – 9015

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1IRSNMR-A157-267[»]
    1K3AX-ray2.10B891-902[»]
    1QQGX-ray2.30A/B4-267[»]
    2Z8CX-ray3.25B731-736[»]
    ProteinModelPortaliP35568.
    SMRiP35568. Positions 11-267.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP35568.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini12 – 115104PHPROSITE-ProRule annotationAdd
    BLAST
    Domaini160 – 264105IRS-type PTBPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni3 – 137135Mediates interaction with PHIPBy similarityAdd
    BLAST
    Regioni896 – 8983GRB2-bindingBy similarity

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi465 – 4684YXXM motif 1
    Motifi551 – 5544YXXM motif 2
    Motifi612 – 6154YXXM motif 3
    Motifi632 – 6354YXXM motif 4
    Motifi662 – 6654YXXM motif 5
    Motifi732 – 7354YXXM motif 6
    Motifi941 – 9444YXXM motif 7
    Motifi989 – 9924YXXM motif 8
    Motifi1012 – 10154YXXM motif 9

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi128 – 1347Poly-Gly
    Compositional biasi268 – 444177Ser-richAdd
    BLAST
    Compositional biasi680 – 6867Poly-Ser
    Compositional biasi807 – 8159Poly-Ser
    Compositional biasi877 – 8826Poly-Gln
    Compositional biasi1192 – 121019Pro-richAdd
    BLAST

    Sequence similaritiesi

    Contains 1 IRS-type PTB domain.PROSITE-ProRule annotation
    Contains 1 PH domain.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiNOG81285.
    HOGENOMiHOG000113103.
    HOVERGENiHBG000542.
    InParanoidiP35568.
    KOiK16172.
    OMAiEYTEMMP.
    OrthoDBiEOG7XM2X6.
    PhylomeDBiP35568.
    TreeFamiTF325994.

    Family and domain databases

    Gene3Di2.30.29.30. 2 hits.
    InterProiIPR002404. Insln_rcpt_S1.
    IPR001849. PH_domain.
    IPR011993. PH_like_dom.
    [Graphical view]
    PfamiPF02174. IRS. 1 hit.
    PF00169. PH. 1 hit.
    [Graphical view]
    PRINTSiPR00628. INSULINRSI.
    SMARTiSM00233. PH. 1 hit.
    SM00310. PTBI. 1 hit.
    [Graphical view]
    PROSITEiPS51064. IRS_PTB. 1 hit.
    PS50003. PH_DOMAIN. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P35568-1 [UniParc]FASTAAdd to Basket

    « Hide

    MASPPESDGF SDVRKVGYLR KPKSMHKRFF VLRAASEAGG PARLEYYENE     50
    KKWRHKSSAP KRSIPLESCF NINKRADSKN KHLVALYTRD EHFAIAADSE 100
    AEQDSWYQAL LQLHNRAKGH HDGAAALGAG GGGGSCSGSS GLGEAGEDLS 150
    YGDVPPGPAF KEVWQVILKP KGLGQTKNLI GIYRLCLTSK TISFVKLNSE 200
    AAAVVLQLMN IRRCGHSENF FFIEVGRSAV TGPGEFWMQV DDSVVAQNMH 250
    ETILEAMRAM SDEFRPRSKS QSSSNCSNPI SVPLRRHHLN NPPPSQVGLT 300
    RRSRTESITA TSPASMVGGK PGSFRVRASS DGEGTMSRPA SVDGSPVSPS 350
    TNRTHAHRHR GSARLHPPLN HSRSIPMPAS RCSPSATSPV SLSSSSTSGH 400
    GSTSDCLFPR RSSASVSGSP SDGGFISSDE YGSSPCDFRS SFRSVTPDSL 450
    GHTPPARGEE ELSNYICMGG KGPSTLTAPN GHYILSRGGN GHRCTPGTGL 500
    GTSPALAGDE AASAADLDNR FRKRTHSAGT SPTITHQKTP SQSSVASIEE 550
    YTEMMPAYPP GGGSGGRLPG HRHSAFVPTR SYPEEGLEMH PLERRGGHHR 600
    PDSSTLHTDD GYMPMSPGVA PVPSGRKGSG DYMPMSPKSV SAPQQIINPI 650
    RRHPQRVDPN GYMMMSPSGG CSPDIGGGPS SSSSSSNAVP SGTSYGKLWT 700
    NGVGGHHSHV LPHPKPPVES SGGKLLPCTG DYMNMSPVGD SNTSSPSDCY 750
    YGPEDPQHKP VLSYYSLPRS FKHTQRPGEP EEGARHQHLR LSTSSGRLLY 800
    AATADDSSSS TSSDSLGGGY CGARLEPSLP HPHHQVLQPH LPRKVDTAAQ 850
    TNSRLARPTR LSLGDPKAST LPRAREQQQQ QQPLLHPPEP KSPGEYVNIE 900
    FGSDQSGYLS GPVAFHSSPS VRCPSQLQPA PREEETGTEE YMKMDLGPGR 950
    RAAWQESTGV EMGRLGPAPP GAASICRPTR AVPSSRGDYM TMQMSCPRQS 1000
    YVDTSPAAPV SYADMRTGIA AEEVSLPRAT MAAASSSSAA SASPTGPQGA 1050
    AELAAHSSLL GGPQGPGGMS AFTRVNLSPN RNQSAKVIRA DPQGCRRRHS 1100
    SETFSSTPSA TRVGNTVPFG AGAAVGGGGG SSSSSEDVKR HSSASFENVW 1150
    LRPGELGGAP KEPAKLCGAA GGLENGLNYI DLDLVKDFKQ CPQECTPEPQ 1200
    PPPPPPPHQP LGSGESSSTR RSSEDLSAYA SISFQKQPED RQ 1242
    Length:1,242
    Mass (Da):131,591
    Last modified:June 1, 1994 - v1
    Checksum:i3C0EFD9E32B3E64A
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti134 – 1341G → GG in AAB21608. (PubMed:1311924)Curated
    Sequence conflicti362 – 3621S → R in AAB21608. (PubMed:1311924)Curated
    Sequence conflicti384 – 3841P → R in AAB21608. (PubMed:1311924)Curated

    Polymorphismi

    The Arg-971 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI3K/AKT1/GSK3 signaling pathway. The polymorphism at Arg-971 may contribute to the in vivo insulin resistance observed in carriers of this variant. Arg-971 could contribute to the risk for atherosclerotic cardiovascular diseases associated with non-insulin-dependent diabetes mellitus (NIDDM) by producing a cluster of insulin resistance-related metabolic abnormalities. In insulin-stimulated human endothelial cells from carriers of the Arg-971 polymorphism, genetic impairment of the IRS1/PI3K/PDPK1/AKT1 insulin signaling cascade results in impaired insulin-stimulated nitric oxide (NO) release and suggested that this may be a mechanism through which the Arg-971 polymorphism contributes to the genetic predisposition to develop endothelial dysfunction and cardiovascular disease. The Arg-971 polymorphism not only reduces phosphorylation of the substrate but allows IRS1 to act as an inhibitor of PI3K, producing global insulin resistance.

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti158 – 1581P → R.
    Corresponds to variant rs1801108 [ dbSNP | Ensembl ].
    VAR_014853
    Natural varianti209 – 2091M → T.
    Corresponds to variant rs1801118 [ dbSNP | Ensembl ].
    VAR_014854
    Natural varianti512 – 5121A → P.1 Publication
    Corresponds to variant rs1801276 [ dbSNP | Ensembl ].
    VAR_005299
    Natural varianti608 – 6081T → R May contribute to insulin resistance by impairing metabolic signaling through PI3K-dependent pathways. 1 Publication
    VAR_025320
    Natural varianti723 – 7231Missing in NIDDM. 1 Publication
    VAR_005301
    Natural varianti809 – 8091S → F.
    Corresponds to variant rs1801120 [ dbSNP | Ensembl ].
    VAR_014855
    Natural varianti892 – 8921S → G.
    Corresponds to variant rs1801277 [ dbSNP | Ensembl ].
    VAR_014856
    Natural varianti971 – 9711G → R.4 Publications
    Corresponds to variant rs1801278 [ dbSNP | Ensembl ].
    VAR_005300
    Natural varianti1043 – 10431S → Y in NIDDM. 1 Publication
    VAR_005302
    Natural varianti1095 – 10951C → Y in NIDDM. 1 Publication
    VAR_005303
    Natural varianti1137 – 11371D → N.
    Corresponds to variant rs3731594 [ dbSNP | Ensembl ].
    VAR_021837

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    S85963 Genomic DNA. Translation: AAB21608.1.
    S62539 mRNA. Translation: AAB27175.1.
    BC053895 mRNA. Translation: AAH53895.1.
    CCDSiCCDS2463.1.
    PIRiI53160. JS0670.
    RefSeqiNP_005535.1. NM_005544.2.
    XP_005246591.1. XM_005246534.2.
    XP_006712575.1. XM_006712512.1.
    UniGeneiHs.471508.

    Genome annotation databases

    EnsembliENST00000305123; ENSP00000304895; ENSG00000169047.
    GeneIDi3667.
    KEGGihsa:3667.
    UCSCiuc002voh.4. human.

    Polymorphism databases

    DMDMi547738.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    S85963 Genomic DNA. Translation: AAB21608.1 .
    S62539 mRNA. Translation: AAB27175.1 .
    BC053895 mRNA. Translation: AAH53895.1 .
    CCDSi CCDS2463.1.
    PIRi I53160. JS0670.
    RefSeqi NP_005535.1. NM_005544.2.
    XP_005246591.1. XM_005246534.2.
    XP_006712575.1. XM_006712512.1.
    UniGenei Hs.471508.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1IRS NMR - A 157-267 [» ]
    1K3A X-ray 2.10 B 891-902 [» ]
    1QQG X-ray 2.30 A/B 4-267 [» ]
    2Z8C X-ray 3.25 B 731-736 [» ]
    ProteinModelPortali P35568.
    SMRi P35568. Positions 11-267.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 109874. 59 interactions.
    DIPi DIP-523N.
    IntActi P35568. 20 interactions.
    MINTi MINT-149537.
    STRINGi 9606.ENSP00000304895.

    PTM databases

    PhosphoSitei P35568.

    Polymorphism databases

    DMDMi 547738.

    Proteomic databases

    MaxQBi P35568.
    PaxDbi P35568.
    PRIDEi P35568.

    Protocols and materials databases

    DNASUi 3667.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000305123 ; ENSP00000304895 ; ENSG00000169047 .
    GeneIDi 3667.
    KEGGi hsa:3667.
    UCSCi uc002voh.4. human.

    Organism-specific databases

    CTDi 3667.
    GeneCardsi GC02M227563.
    HGNCi HGNC:6125. IRS1.
    HPAi CAB005261.
    HPA046433.
    HPA050221.
    MIMi 125853. phenotype.
    147545. gene.
    neXtProti NX_P35568.
    PharmGKBi PA203.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG81285.
    HOGENOMi HOG000113103.
    HOVERGENi HBG000542.
    InParanoidi P35568.
    KOi K16172.
    OMAi EYTEMMP.
    OrthoDBi EOG7XM2X6.
    PhylomeDBi P35568.
    TreeFami TF325994.

    Enzyme and pathway databases

    Reactomei REACT_111133. Growth hormone receptor signaling.
    REACT_12464. PI3K/AKT activation.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_150203. IRS-related events triggered by IGF1R.
    REACT_169118. Signaling by Leptin.
    REACT_508. Signal attenuation.
    REACT_524. SOS-mediated signalling.
    REACT_570. IRS activation.
    REACT_75829. PIP3 activates AKT signaling.
    REACT_976. PI3K Cascade.
    SignaLinki P35568.

    Miscellaneous databases

    EvolutionaryTracei P35568.
    GeneWikii IRS1.
    GenomeRNAii 3667.
    NextBioi 14355.
    PMAP-CutDB P35568.
    PROi P35568.
    SOURCEi Search...

    Gene expression databases

    Bgeei P35568.
    CleanExi HS_IRS1.
    Genevestigatori P35568.

    Family and domain databases

    Gene3Di 2.30.29.30. 2 hits.
    InterProi IPR002404. Insln_rcpt_S1.
    IPR001849. PH_domain.
    IPR011993. PH_like_dom.
    [Graphical view ]
    Pfami PF02174. IRS. 1 hit.
    PF00169. PH. 1 hit.
    [Graphical view ]
    PRINTSi PR00628. INSULINRSI.
    SMARTi SM00233. PH. 1 hit.
    SM00310. PTBI. 1 hit.
    [Graphical view ]
    PROSITEi PS51064. IRS_PTB. 1 hit.
    PS50003. PH_DOMAIN. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Human skeletal muscle insulin receptor substrate-1. Characterization of the cDNA, gene, and chromosomal localization."
      Araki E., Sun X.J., Haag B.L. III, Chuang L.M., Zhang Y., Yang-Feng T.L., White M.F., Kahn C.R.
      Diabetes 42:1041-1054(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Skeletal muscle.
    2. "Cloning and increased expression of an insulin receptor substrate-1-like gene in human hepatocellular carcinoma."
      Nishiyama M., Wands J.R.
      Biochem. Biophys. Res. Commun. 183:280-285(1992) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Eye.
    4. "The insulin receptor substrate (IRS-1) is a PEST protein that is susceptible to calpain degradation in vitro."
      Smith L.K., Bradshaw M., Croall D.E., Garner C.W.
      Biochem. Biophys. Res. Commun. 196:767-772(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: TURNOVER.
    5. "Non-SH2 domains within insulin receptor substrate-1 and SHC mediate their phosphotyrosine-dependent interaction with the NPEY motif of the insulin-like growth factor I receptor."
      Craparo A., O'Neill T.J., Gustafson T.A.
      J. Biol. Chem. 270:15639-15643(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH IGF1R.
    6. "Distinct modes of interaction of SHC and insulin receptor substrate-1 with the insulin receptor NPEY region via non-SH2 domains."
      He W., O'Neill T.J., Gustafson T.A.
      J. Biol. Chem. 270:23258-23262(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH INSR.
    7. "Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain."
      Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.
      Mol. Cell. Biol. 15:2500-2508(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH INSR.
    8. "Adipose-specific expression, phosphorylation of Ser794 in insulin receptor substrate-1, and activation in diabetic animals of salt-inducible kinase-2."
      Horike N., Takemori H., Katoh Y., Doi J., Min L., Asano T., Sun X.J., Yamamoto H., Kasayama S., Muraoka M., Nonaka Y., Okamoto M.
      J. Biol. Chem. 278:18440-18447(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: MUTAGENESIS OF SER-794, PHOSPHORYLATION AT SER-794.
    9. "Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101)."
      Li Y., Soos T.J., Li X., Wu J., Degennaro M., Sun X., Littman D.R., Birnbaum M.J., Polakiewicz R.D.
      J. Biol. Chem. 279:45304-45307(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-1101.
    10. "ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth."
      Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T.
      J. Cell Sci. 117:3319-3329(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION BY ALK, INTERACTION WITH ALK.
    11. "Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans."
      Banks A.S., Li J., McKeag L., Hribal M.L., Kashiwada M., Accili D., Rothman P.B.
      J. Clin. Invest. 115:2462-2471(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH SOCS7.
    12. "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."
      Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J.
      Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-662, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    13. "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
      Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
      Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-629 AND SER-636, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    14. "Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase."
      Kuo A.H., Stoica G.E., Riegel A.T., Wellstein A.
      Oncogene 26:859-869(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ALK, FUNCTION.
    15. "S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2."
      Zhang J., Gao Z., Yin J., Quon M.J., Ye J.
      J. Biol. Chem. 283:35375-35382(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-270; SER-307; SER-636 AND SER-1101.
    16. "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis."
      Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III
      J. Proteome Res. 7:1346-1351(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    17. "The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation."
      Xu X., Sarikas A., Dias-Santagata D.C., Dolios G., Lafontant P.J., Tsai S.C., Zhu W., Nakajima H., Nakajima H.O., Field L.J., Wang R., Pan Z.Q.
      Mol. Cell 30:403-414(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION, PHOSPHORYLATION AT SER-307; SER-312; SER-527 AND SER-636, MUTAGENESIS OF SER-307; SER-312; SER-527; SER-636 AND SER-639.
    18. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    19. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
      Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
      Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-348, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Leukemic T-cell.
    20. "The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in HepG2 cells."
      Yang X., Nath A., Opperman M.J., Chan C.
      Mol. Biol. Cell 21:3449-3458(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-312 AND TYR-941.
    21. "Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain."
      Zhou M.-M., Huang B., Olejniczak E.T., Meadows R.P., Shuker S.B., Miyazaki M., Trueb T., Shoelson S.E., Fesik S.W.
      Nat. Struct. Biol. 3:388-393(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE BY NMR OF 157-267.
    22. "Crystal structure of the pleckstrin homology-phosphotyrosine binding (PH-PTB) targeting region of insulin receptor substrate 1."
      Dhe-Paganon S., Ottinger E.A., Nolte R.T., Eck M.J., Shoelson S.E.
      Proc. Natl. Acad. Sci. U.S.A. 96:8378-8383(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 4-267.
    23. "Structure and autoregulation of the insulin-like growth factor 1 receptor kinase."
      Favelyukis S., Till J.H., Hubbard S.R., Miller W.T.
      Nat. Struct. Biol. 8:1058-1063(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 889-902 IN COMPLEX WITH IGF1R.
    24. "Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus."
      Almind K., Bjoerbaek C., Vestergaard H., Hansen T., Echwald S., Pedersen O.
      Lancet 342:828-832(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS PRO-512 AND ARG-971.
    25. "Deletion of Gly723 in the insulin receptor substrate-1 of a patient with noninsulin-dependent diabetes mellitus."
      Esposito D.L., Mammarella S., Ranieri A., della Loggia F., Capani F., Consoli A., Mariani-Costantini R., Caramia F.G., Cama A., Battista P.
      Hum. Mutat. 7:364-366(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT NIDDM GLY-723 DEL.
    26. "Novel allele of the insulin receptor substrate-1 bearing two non-conservative amino acid substitutions in a patient with noninsulin-dependent diabetes mellitus."
      Mammarella S., Creati B., Esposito D.L., Arcuri P., della Loggia F., Capani F., Mariani-Costantini R., Caramia F.G., Battista P., Cama A.
      Hum. Mutat. 11:411-411(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS NIDDM TYR-1043 AND TYR-1095.
    27. "The Gly-->Arg(972) amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells."
      Hribal M.L., Federici M., Porzio O., Lauro D., Borboni P., Accili D., Lauro R., Sesti G.
      J. Clin. Endocrinol. Metab. 85:2004-2013(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERIZATION OF VARIANT ARG-971.
    28. "The Arg(972) variant in insulin receptor substrate-1 is associated with an atherogenic profile in offspring of type 2 diabetic patients."
      Marini M.A., Frontoni S., Mineo D., Bracaglia D., Cardellini M., De Nicolais P., Baroni A., D'Alfonso R., Perna M., Lauro D., Federici M., Gambardella S., Lauro R., Sesti G.
      J. Clin. Endocrinol. Metab. 88:3368-3371(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: ASSOCIATION OF VARIANT ARG-971 WITH NIDDM.
    29. "Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance."
      Abate N., Carulli L., Cabo-Chan A. Jr., Chandalia M., Snell P.G., Grundy S.M.
      J. Clin. Endocrinol. Metab. 88:5927-5934(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT ARG-971.
    30. "A novel T608R missense mutation in insulin receptor substrate-1 identified in a subject with type 2 diabetes impairs metabolic insulin signaling."
      Esposito D.L., Li Y., Vanni C., Mammarella S., Veschi S., Della Loggia F., Mariani-Costantini R., Battista P., Quon M.J., Cama A.
      J. Clin. Endocrinol. Metab. 88:1468-1475(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT ARG-608, CHARACTERIZATION OF VARIANT ARG-608.
    31. "G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells."
      Federici M., Pandolfi A., De Filippis E.A., Pellegrini G., Menghini R., Lauro D., Cardellini M., Romano M., Sesti G., Lauro R., Consoli A.
      Circulation 109:399-405(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT ARG-971, ASSOCIATION WITH ENDOTHELIAL DYSFUNCTION, CARDIOVASCULAR DISEASE.
    32. "Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 to associate with the insulin receptor and inhibit receptor autophosphorylation."
      McGettrick A.J., Feener E.P., Kahn C.R.
      J. Biol. Chem. 280:6441-6446(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT ARG-971, MOLECULAR MECHANISM OF LINKAGE TO NIDDM.

    Entry informationi

    Entry nameiIRS1_HUMAN
    AccessioniPrimary (citable) accession number: P35568
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: June 1, 1994
    Last sequence update: June 1, 1994
    Last modified: October 1, 2014
    This is version 162 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 2
      Human chromosome 2: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

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