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P35568 (IRS1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 160. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Insulin receptor substrate 1

Short name=IRS-1
Gene names
Name:IRS1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1242 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.14 Ref.30

Subunit structure

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. Ref.5 Ref.6 Ref.7 Ref.10 Ref.11 Ref.14

Post-translational modification

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. Ref.8 Ref.9 Ref.10 Ref.15 Ref.19

Polymorphism

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.

Involvement in disease

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.
Note: The gene represented in this entry may be involved in disease pathogenesis. Ref.24 Ref.25 Ref.27 Ref.30 Ref.31

Sequence similarities

Contains 1 IRS-type PTB domain.

Contains 1 PH domain.

Ontologies

Keywords
   Coding sequence diversityPolymorphism
   DiseaseDiabetes mellitus
Disease mutation
   DomainRepeat
   Molecular functionTransducer
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processFc-epsilon receptor signaling pathway

Traceable author statement. Source: Reactome

JAK-STAT cascade involved in growth hormone signaling pathway

Traceable author statement. Source: Reactome

cellular response to insulin stimulus

Inferred from mutant phenotype PubMed 16814735. Source: BHF-UCL

epidermal growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

fibroblast growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

glucose homeostasis

Traceable author statement PubMed 16814735. Source: BHF-UCL

innate immune response

Traceable author statement. Source: Reactome

insulin receptor signaling pathway

Inferred from physical interaction Ref.7Ref.6. Source: UniProtKB

insulin-like growth factor receptor signaling pathway

Inferred from physical interaction Ref.5. Source: UniProtKB

lipid catabolic process

Inferred from electronic annotation. Source: Ensembl

mammary gland development

Inferred from electronic annotation. Source: Ensembl

negative regulation of insulin receptor signaling pathway

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of insulin secretion

Inferred from direct assay PubMed 15572028. Source: BHF-UCL

neurotrophin TRK receptor signaling pathway

Traceable author statement. Source: Reactome

phosphatidylinositol 3-kinase signaling

Inferred from direct assay PubMed 7782332. Source: BHF-UCL

phosphatidylinositol-mediated signaling

Traceable author statement. Source: Reactome

positive regulation of cell migration

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell proliferation

Non-traceable author statement PubMed 17925406. Source: BHF-UCL

positive regulation of fatty acid beta-oxidation

Inferred from mutant phenotype PubMed 16814735. Source: BHF-UCL

positive regulation of glucose import

Inferred from mutant phenotype PubMed 16814735. Source: BHF-UCL

positive regulation of glucose import in response to insulin stimulus

Inferred from direct assay PubMed 7493946. Source: BHF-UCL

positive regulation of glucose metabolic process

Inferred from mutant phenotype PubMed 16814735. Source: BHF-UCL

positive regulation of glycogen biosynthetic process

Inferred from mutant phenotype PubMed 16814735. Source: BHF-UCL

positive regulation of insulin receptor signaling pathway

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of mesenchymal cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of phosphatidylinositol 3-kinase activity

Inferred from sequence or structural similarity. Source: BHF-UCL

protein kinase B signaling

Inferred from electronic annotation. Source: Ensembl

protein localization to nucleus

Inferred from electronic annotation. Source: Ensembl

regulation of gene expression

Inferred from electronic annotation. Source: Ensembl

response to insulin

Inferred from direct assay PubMed 16516141. Source: BHF-UCL

response to peptide hormone

Inferred from sequence or structural similarity. Source: BHF-UCL

signal transduction

Traceable author statement Ref.2. Source: ProtInc

   Cellular_componentcaveola

Inferred from direct assay PubMed 15182363. Source: BHF-UCL

cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

insulin receptor complex

Inferred from sequence or structural similarity. Source: BHF-UCL

intracellular membrane-bounded organelle

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

plasma membrane

Traceable author statement. Source: Reactome

   Molecular_functionSH2 domain binding

Inferred from sequence or structural similarity. Source: UniProtKB

insulin receptor binding

Inferred from physical interaction Ref.7Ref.6. Source: UniProtKB

insulin-like growth factor receptor binding

Inferred from physical interaction Ref.5. Source: UniProtKB

phosphatidylinositol 3-kinase binding

Inferred from physical interaction PubMed 16043515. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 11018022Ref.15Ref.6PubMed 8388384PubMed 9295312. Source: UniProtKB

protein kinase C binding

Inferred from sequence or structural similarity. Source: BHF-UCL

signal transducer activity

Traceable author statement Ref.2Ref.1. Source: ProtInc

transmembrane receptor protein tyrosine kinase adaptor activity

Inferred from sequence or structural similarity. Source: BHF-UCL

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 12421242Insulin receptor substrate 1
PRO_0000084236

Regions

Domain12 – 115104PH
Domain160 – 264105IRS-type PTB
Region3 – 137135Mediates interaction with PHIP By similarity
Region896 – 8983GRB2-binding By similarity
Motif465 – 4684YXXM motif 1
Motif551 – 5544YXXM motif 2
Motif612 – 6154YXXM motif 3
Motif632 – 6354YXXM motif 4
Motif662 – 6654YXXM motif 5
Motif732 – 7354YXXM motif 6
Motif941 – 9444YXXM motif 7
Motif989 – 9924YXXM motif 8
Motif1012 – 10154YXXM motif 9
Compositional bias128 – 1347Poly-Gly
Compositional bias268 – 444177Ser-rich
Compositional bias680 – 6867Poly-Ser
Compositional bias807 – 8159Poly-Ser
Compositional bias877 – 8826Poly-Gln
Compositional bias1192 – 121019Pro-rich

Amino acid modifications

Modified residue991Phosphoserine; by CK2 By similarity
Modified residue2701Phosphoserine; by RPS6KB1 Ref.15
Modified residue3071Phosphoserine; by RPS6KB1 Ref.15
Modified residue3121Phosphoserine; by IKKB and MAPK8 Ref.19
Modified residue3451Phosphoserine By similarity
Modified residue3481Phosphoserine Ref.18
Modified residue4651Phosphotyrosine; by INSR By similarity
Modified residue6121Phosphotyrosine; by INSR
Modified residue6291Phosphoserine Ref.13
Modified residue6321Phosphotyrosine; by INSR
Modified residue6361Phosphoserine Ref.13 Ref.15
Modified residue6621Phosphotyrosine Ref.12
Modified residue7941Phosphoserine; by AMPK and SIK2 Ref.8
Modified residue8961Phosphotyrosine; by INSR By similarity
Modified residue9411Phosphotyrosine; by INSR Ref.19
Modified residue9891Phosphotyrosine; by INSR By similarity
Modified residue11011Phosphoserine; by RPS6KB1 and PKC/PRKCQ Ref.9 Ref.15
Modified residue11791Phosphotyrosine; by INSR By similarity
Modified residue12291Phosphotyrosine; by INSR By similarity

Natural variations

Natural variant1581P → R.
Corresponds to variant rs1801108 [ dbSNP | Ensembl ].
VAR_014853
Natural variant2091M → T.
Corresponds to variant rs1801118 [ dbSNP | Ensembl ].
VAR_014854
Natural variant5121A → P. Ref.23
Corresponds to variant rs1801276 [ dbSNP | Ensembl ].
VAR_005299
Natural variant6081T → R May contribute to insulin resistance by impairing metabolic signaling through PI3K-dependent pathways. Ref.29
VAR_025320
Natural variant7231Missing in NIDDM. Ref.24
VAR_005301
Natural variant8091S → F.
Corresponds to variant rs1801120 [ dbSNP | Ensembl ].
VAR_014855
Natural variant8921S → G.
Corresponds to variant rs1801277 [ dbSNP | Ensembl ].
VAR_014856
Natural variant9711G → R. Ref.23 Ref.26 Ref.27 Ref.28 Ref.30 Ref.31
Corresponds to variant rs1801278 [ dbSNP | Ensembl ].
VAR_005300
Natural variant10431S → Y in NIDDM. Ref.25
VAR_005302
Natural variant10951C → Y in NIDDM. Ref.25
VAR_005303
Natural variant11371D → N.
Corresponds to variant rs3731594 [ dbSNP | Ensembl ].
VAR_021837

Experimental info

Mutagenesis7941S → A: Loss of phosphorylation by SIK2. Ref.8
Sequence conflict1341G → GG in AAB21608. Ref.2
Sequence conflict3621S → R in AAB21608. Ref.2
Sequence conflict3841P → R in AAB21608. Ref.2

Secondary structure

......................................... 1242
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P35568 [UniParc].

Last modified June 1, 1994. Version 1.
Checksum: 3C0EFD9E32B3E64A

FASTA1,242131,591
        10         20         30         40         50         60 
MASPPESDGF SDVRKVGYLR KPKSMHKRFF VLRAASEAGG PARLEYYENE KKWRHKSSAP 

        70         80         90        100        110        120 
KRSIPLESCF NINKRADSKN KHLVALYTRD EHFAIAADSE AEQDSWYQAL LQLHNRAKGH 

       130        140        150        160        170        180 
HDGAAALGAG GGGGSCSGSS GLGEAGEDLS YGDVPPGPAF KEVWQVILKP KGLGQTKNLI 

       190        200        210        220        230        240 
GIYRLCLTSK TISFVKLNSE AAAVVLQLMN IRRCGHSENF FFIEVGRSAV TGPGEFWMQV 

       250        260        270        280        290        300 
DDSVVAQNMH ETILEAMRAM SDEFRPRSKS QSSSNCSNPI SVPLRRHHLN NPPPSQVGLT 

       310        320        330        340        350        360 
RRSRTESITA TSPASMVGGK PGSFRVRASS DGEGTMSRPA SVDGSPVSPS TNRTHAHRHR 

       370        380        390        400        410        420 
GSARLHPPLN HSRSIPMPAS RCSPSATSPV SLSSSSTSGH GSTSDCLFPR RSSASVSGSP 

       430        440        450        460        470        480 
SDGGFISSDE YGSSPCDFRS SFRSVTPDSL GHTPPARGEE ELSNYICMGG KGPSTLTAPN 

       490        500        510        520        530        540 
GHYILSRGGN GHRCTPGTGL GTSPALAGDE AASAADLDNR FRKRTHSAGT SPTITHQKTP 

       550        560        570        580        590        600 
SQSSVASIEE YTEMMPAYPP GGGSGGRLPG HRHSAFVPTR SYPEEGLEMH PLERRGGHHR 

       610        620        630        640        650        660 
PDSSTLHTDD GYMPMSPGVA PVPSGRKGSG DYMPMSPKSV SAPQQIINPI RRHPQRVDPN 

       670        680        690        700        710        720 
GYMMMSPSGG CSPDIGGGPS SSSSSSNAVP SGTSYGKLWT NGVGGHHSHV LPHPKPPVES 

       730        740        750        760        770        780 
SGGKLLPCTG DYMNMSPVGD SNTSSPSDCY YGPEDPQHKP VLSYYSLPRS FKHTQRPGEP 

       790        800        810        820        830        840 
EEGARHQHLR LSTSSGRLLY AATADDSSSS TSSDSLGGGY CGARLEPSLP HPHHQVLQPH 

       850        860        870        880        890        900 
LPRKVDTAAQ TNSRLARPTR LSLGDPKAST LPRAREQQQQ QQPLLHPPEP KSPGEYVNIE 

       910        920        930        940        950        960 
FGSDQSGYLS GPVAFHSSPS VRCPSQLQPA PREEETGTEE YMKMDLGPGR RAAWQESTGV 

       970        980        990       1000       1010       1020 
EMGRLGPAPP GAASICRPTR AVPSSRGDYM TMQMSCPRQS YVDTSPAAPV SYADMRTGIA 

      1030       1040       1050       1060       1070       1080 
AEEVSLPRAT MAAASSSSAA SASPTGPQGA AELAAHSSLL GGPQGPGGMS AFTRVNLSPN 

      1090       1100       1110       1120       1130       1140 
RNQSAKVIRA DPQGCRRRHS SETFSSTPSA TRVGNTVPFG AGAAVGGGGG SSSSSEDVKR 

      1150       1160       1170       1180       1190       1200 
HSSASFENVW LRPGELGGAP KEPAKLCGAA GGLENGLNYI DLDLVKDFKQ CPQECTPEPQ 

      1210       1220       1230       1240 
PPPPPPPHQP LGSGESSSTR RSSEDLSAYA SISFQKQPED RQ 

« Hide

References

« Hide 'large scale' references
[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]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[18]"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.
[19]"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.
[20]"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.
[21]"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.
[22]"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.
[23]"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.
[24]"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.
[25]"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.
[26]"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.
[27]"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.
[28]"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.
[29]"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.
[30]"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.
[31]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
S85963 Genomic DNA. Translation: AAB21608.1.
S62539 mRNA. Translation: AAB27175.1.
BC053895 mRNA. Translation: AAH53895.1.
CCDSCCDS2463.1.
PIRJS0670. I53160.
RefSeqNP_005535.1. NM_005544.2.
XP_005246591.1. XM_005246534.2.
XP_006712575.1. XM_006712512.1.
UniGeneHs.471508.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1IRSNMR-A157-267[»]
1K3AX-ray2.10B891-902[»]
1QQGX-ray2.30A/B4-267[»]
2Z8CX-ray3.25B731-736[»]
ProteinModelPortalP35568.
SMRP35568. Positions 11-267.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109874. 58 interactions.
DIPDIP-523N.
IntActP35568. 19 interactions.
MINTMINT-149537.
STRING9606.ENSP00000304895.

PTM databases

PhosphoSiteP35568.

Polymorphism databases

DMDM547738.

Proteomic databases

MaxQBP35568.
PaxDbP35568.
PRIDEP35568.

Protocols and materials databases

DNASU3667.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000305123; ENSP00000304895; ENSG00000169047.
GeneID3667.
KEGGhsa:3667.
UCSCuc002voh.4. human.

Organism-specific databases

CTD3667.
GeneCardsGC02M227563.
HGNCHGNC:6125. IRS1.
HPACAB005261.
HPA046433.
HPA050221.
MIM125853. phenotype.
147545. gene.
neXtProtNX_P35568.
PharmGKBPA203.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG81285.
HOGENOMHOG000113103.
HOVERGENHBG000542.
InParanoidP35568.
KOK16172.
OMAEYTEMMP.
OrthoDBEOG7XM2X6.
PhylomeDBP35568.
TreeFamTF325994.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.
SignaLinkP35568.

Gene expression databases

BgeeP35568.
CleanExHS_IRS1.
GenevestigatorP35568.

Family and domain databases

Gene3D2.30.29.30. 2 hits.
InterProIPR002404. Insln_rcpt_S1.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
[Graphical view]
PfamPF02174. IRS. 1 hit.
PF00169. PH. 1 hit.
[Graphical view]
PRINTSPR00628. INSULINRSI.
SMARTSM00233. PH. 1 hit.
SM00310. PTBI. 1 hit.
[Graphical view]
PROSITEPS51064. IRS_PTB. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP35568.
GeneWikiIRS1.
GenomeRNAi3667.
NextBio14355.
PMAP-CutDBP35568.
PROP35568.
SOURCESearch...

Entry information

Entry nameIRS1_HUMAN
AccessionPrimary (citable) accession number: P35568
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: June 1, 1994
Last modified: July 9, 2014
This is version 160 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM