Insulin receptor substrate 1 - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot P35568 (IRS1_HUMAN)

Last modified February 9, 2010. Version 117. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
Insulin receptor substrate 1
Short name=IRS-1

Gene names

Name:

IRS1

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	1242 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

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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.28
Subunit structure	Interacts with the NPXY motif of tyrosine-phosphorylated IGF1R and INSR via the PTB domain. Binds to phosphatidylinositol 3-kinase p85 subunit via the phosphorylated YXXM motifs. Binds ROCK1. Binds to UBTF and PIK3CA in nuclear extracts By similarity. Interacts with SOCS7. Ref.5 Ref.6 Ref.7 Ref.9
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.
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	Polymorphisms in IRS1 may be involved in the etiology of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853]. Ref.28 Ref.22 Ref.23 Ref.25 Ref.29
Sequence similarities	Contains 1 IRS-type PTB domain. Contains 1 PH domain.

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Ontologies

Keywords
Coding sequence diversity	Polymorphism
Disease	Diabetes mellitus Disease mutation
Domain	Repeat
Molecular function	Transducer
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	glucose homeostasis Traceable author statement. Source: UniProtKB insulin receptor signaling pathway Ref.6 Ref.7 Inferred from physical interaction. Source: UniProtKB insulin-like growth factor receptor signaling pathway Ref.5 Inferred from physical interaction. Source: UniProtKB negative regulation of insulin receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB phosphoinositide 3-kinase cascade Inferred from direct assay. Source: UniProtKB positive regulation of fatty acid beta-oxidation Inferred from mutant phenotype. Source: UniProtKB positive regulation of glucose import Inferred from mutant phenotype. Source: UniProtKB positive regulation of glucose metabolic process Inferred from mutant phenotype. Source: UniProtKB positive regulation of glycogen biosynthetic process Inferred from mutant phenotype. Source: UniProtKB positive regulation of insulin receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of phosphoinositide 3-kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	caveola Inferred from direct assay. Source: UniProtKB cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB insulin receptor complex Inferred from sequence or structural similarity. Source: UniProtKB microsome Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	SH2 domain binding Inferred from sequence or structural similarity. Source: UniProtKB insulin receptor binding Ref.6 Ref.7 Inferred from physical interaction. Source: UniProtKB insulin-like growth factor receptor binding Ref.5 Inferred from physical interaction. Source: UniProtKB phosphoinositide 3-kinase binding Inferred from physical interaction. Source: UniProtKB protein kinase C binding Inferred from sequence or structural similarity. Source: UniProtKB transmembrane receptor protein tyrosine kinase docking protein activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct	Notes
DDR1	Q08345-2	1	EBI-517592,EBI-711903
Grb2	Q60631	1	EBI-517592,EBI-1688	From a different organism.
Pik3r1	P26450	1	EBI-517592,EBI-641764	From a different organism.

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1242

1242

Insulin receptor substrate 1

PRO_0000084236

Regions

Domain

12 – 115

104

Domain

160 – 264

105

IRS-type PTB

Region

896 – 898

GRB2-binding By similarity

Motif

465 – 468

YXXM motif 1

Motif

551 – 554

YXXM motif 2

Motif

612 – 615

YXXM motif 3

Motif

632 – 635

YXXM motif 4

Motif

662 – 665

YXXM motif 5

Motif

732 – 735

YXXM motif 6

Motif

941 – 944

YXXM motif 7

Motif

989 – 992

YXXM motif 8

Motif

1012 – 1015

YXXM motif 9

Compositional bias

128 – 134

Poly-Gly

Compositional bias

268 – 444

177

Ser-rich

Compositional bias

680 – 686

Poly-Ser

Compositional bias

807 – 815

Poly-Ser

Compositional bias

877 – 882

Poly-Gln

Compositional bias

1192 – 1210

Pro-rich

Amino acid modifications

Modified residue

Phosphoserine By similarity

Modified residue

Phosphotyrosine Ref.10 Ref.12

Modified residue

Phosphoserine; by CK2 By similarity

Modified residue

312

Phosphoserine By similarity

Modified residue

329

Phosphoserine By similarity

Modified residue

345

Phosphoserine By similarity

Modified residue

348

Phosphoserine Ref.17

Modified residue

465

Phosphotyrosine; by INSR By similarity

Modified residue

531

Phosphoserine Ref.13

Modified residue

612

Phosphotyrosine; by INSR Ref.12

Modified residue

629

Phosphoserine Ref.11

Modified residue

632

Phosphotyrosine; by INSR Ref.12 Ref.15

Modified residue

636

Phosphoserine Ref.11

Modified residue

662

Phosphotyrosine Ref.10

Modified residue

794

Phosphoserine; by SNF1LK2 Ref.8

Modified residue

896

Phosphotyrosine; by INSR By similarity

Modified residue

941

Phosphotyrosine; by INSR By similarity

Modified residue

989

Phosphotyrosine; by INSR By similarity

Modified residue

1078

Phosphoserine Ref.14

Modified residue

1101

Phosphoserine Ref.13 Ref.11

Modified residue

1145

Phosphoserine By similarity

Modified residue

1179

Phosphotyrosine; by INSR By similarity

Modified residue

1223

Phosphoserine By similarity

Modified residue

1229

Phosphotyrosine; by INSR By similarity

Natural variations

Natural variant

158

P → R: dbSNP rs1801108.

VAR_014853

Natural variant

209

M → T: dbSNP rs1801118.

VAR_014854

Natural variant

512

A → P: dbSNP rs1801276. Ref.21

VAR_005299

Natural variant

608

T → R May contribute to insulin resistance by impairing metabolic signaling through PI3K-dependent pathways. Ref.27

VAR_025320

Natural variant

723

Missing in NIDDM.

VAR_005301

Natural variant

809

S → F: dbSNP rs1801120.

VAR_014855

Natural variant

892

S → G: dbSNP rs1801277.

VAR_014856

Natural variant

971

G → R: dbSNP rs1801278. Ref.28 Ref.25 Ref.29 Ref.21 Ref.24 Ref.26

VAR_005300

Natural variant

1043

S → Y in NIDDM. Ref.23

VAR_005302

Natural variant

1095

C → Y in NIDDM. Ref.23

VAR_005303

Natural variant

1137

D → N: dbSNP rs3731594.

VAR_021837

Experimental info

Mutagenesis

794

S → A: Loss of phosphorylation by SNF1LK2. Ref.8

Sequence conflict

134

G → GG in AAB21608. Ref.2

Sequence conflict

362

S → R in AAB21608. Ref.2

Sequence conflict

384

P → R in AAB21608. Ref.2

Secondary structure

1242

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P35568-1 [UniParc].

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

1,242

131,591

        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

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References

	« Hide 'large scale' referencesShow '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: 8513971] [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: 1311924] [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: 15489334] [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: 8240352] [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: 7541045] [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: 7559478] [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: 7537849] [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: 12624099] [Abstract] Cited for: MUTAGENESIS OF SER-794, PHOSPHORYLATION AT SER-794.
[9]	"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: 16127460] [Abstract] Cited for: INTERACTION WITH SOCS7.
[10]	"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: 15592455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-46 AND TYR-662, MASS SPECTROMETRY.
[11]	"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: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-629; SER-636 AND SER-1101, MASS SPECTROMETRY. Tissue: Epithelium.
[12]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-46; TYR-612 AND TYR-632, MASS SPECTROMETRY.
[13]	"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: 18220336] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-531 AND SER-1101, MASS SPECTROMETRY.
[14]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1078, MASS SPECTROMETRY.
[15]	"An extensive survey of tyrosine phosphorylation revealing new sites in human mammary epithelial cells." Heibeck T.H., Ding S.-J., Opresko L.K., Zhao R., Schepmoes A.A., Yang F., Tolmachev A.V., Monroe M.E., Camp D.G. II, Smith R.D., Wiley H.S., Qian W.-J. J. Proteome Res. 8:3852-3861(2009) [PubMed: 19534553] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-632, MASS SPECTROMETRY. Tissue: Mammary epithelium.
[16]	"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: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1101, MASS SPECTROMETRY.
[17]	"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: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-348, MASS SPECTROMETRY. Tissue: T-cell.
[18]	"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: 8599766] [Abstract] Cited for: STRUCTURE BY NMR OF 157-267.
[19]	"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: 10411883] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 4-267.
[20]	"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: 11694888] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 889-902 IN COMPLEX WITH IGF1R.
[21]	"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: 8104271] [Abstract] Cited for: VARIANTS PRO-512 AND ARG-971.
[22]	"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: 8723689] [Abstract] Cited for: VARIANT NIDDM GLY-723 DEL.
[23]	"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: 10206679] [Abstract] Cited for: VARIANTS NIDDM TYR-1043 AND TYR-1095.
[24]	"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: 10843189] [Abstract] Cited for: CHARACTERIZATION OF VARIANT ARG-971.
[25]	"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: 12843189] [Abstract] Cited for: ASSOCIATION OF VARIANT ARG-971 WITH NIDDM.
[26]	"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: 14671192] [Abstract] Cited for: VARIANT ARG-971.
[27]	"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: 12679424] [Abstract] Cited for: VARIANT ARG-608, CHARACTERIZATION OF VARIANT ARG-608.
[28]	"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: 14707024] [Abstract] Cited for: VARIANT ARG-971, ASSOCIATION WITH ENDOTHELIAL DYSFUNCTION AND CARDIOVASCULAR DISEASE.
[29]	"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: 15590636] [Abstract] Cited for: VARIANT ARG-971, MOLECULAR MECHANISM OF LINKAGE TO NIDDM.
+	Additional computationally mapped references.

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Cross-references

Sequence databases

EMBL
GenBank
DDBJ

S85963 Genomic DNA. Translation: AAB21608.1.
S62539 mRNA. Translation: AAB27175.1.
BC053895 mRNA. Translation: AAH53895.1.

IPI

IPI00019471.

PIR

JS0670. I53160.

RefSeq

NP_005535.1.

UniGene

Hs.471508

3D structure databases

PDBe
RCSB PDB
PDBj

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	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-523N.

IntAct

P35568. 6 interactions.

STRING

P35568.

PTM databases

PhosphoSite

P35568.

Proteomic databases

PRIDE

P35568.

Genome annotation databases

Ensembl

ENST00000305123; ENSP00000304895; ENSG00000169047; Homo sapiens. [Genome view]

GeneID

3667.

KEGG

hsa:3667.

UCSC

uc002voh.2. human.

Organism-specific databases

CTD

3667.

GeneCards

GC02M227308.

H-InvDB

HIX0024007.

HGNC

HGNC:6125. IRS1.

HPA

CAB005261.

MIM

125853. phenotype.
147545. gene.

PharmGKB

PA203.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG16886.

HOGENOM

HBG443689.

HOVERGEN

P35568.

InParanoid

P35568.

OMA

GCRRRHS.

OrthoDB

EOG9BVVDQ.

PhylomeDB

P35568.

Enzyme and pathway databases

Pathway_Interaction_DB

igf1_pathway. IGF1 pathway.
il2_1pathway. IL2-mediated signaling events.
il4_2pathway. IL4-mediated signaling events.
insulin_pathway. Insulin Pathway.
avb3_integrin_pathway. Integrins in angiogenesis.
mtor_4pathway. mTOR signaling pathway.
s1p_s1p2_pathway. S1P2 pathway.
ptp1bpathway. Signaling events mediated by PTP1B.
ret_pathway. Signaling events regulated by Ret tyrosine kinase.

Reactome

REACT_11061. Signalling by NGF.
REACT_498. Signaling by Insulin receptor.
REACT_508. Signal attenuation.

Gene expression databases

ArrayExpress

P35568.

Bgee

P35568.

CleanEx

HS_IRS1.

Genevestigator

P35568.

GermOnline

ENSG00000169047. Homo sapiens.

Family and domain databases

InterPro

IPR002404. Insln_rcpt_S1.
IPR011993. PH_type.
IPR001849. Pleckstrin_homology.
[Graphical view]

Gene3D

G3DSA:2.30.29.30. PH_type. 2 hits.

Pfam

PF02174. IRS. 1 hit.
PF00169. PH. 1 hit.
[Graphical view]

PRINTS

PR00628. INSULINRSI.

SMART

SM00233. PH. 1 hit.
SM00310. PTBI. 1 hit.
[Graphical view]

PROSITE

PS51064. IRS_PTB. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

14355.

PMAP-CutDB

P35568.

SOURCE

Search...

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Entry information

Entry name

IRS1_HUMAN

Accession

Primary (citable) accession number: P35568

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	February 9, 2010
This is version 117 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.

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Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

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

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Natural variations

Experimental info

Secondary structure

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Proteomic databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

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