P35568 (IRS1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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

Gene names

Name:

IRS1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1242 AA.
Sequence status	Complete.
Protein existence	Evidence 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.
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 diversity	Polymorphism
Disease	Diabetes mellitus Disease mutation
Domain	Repeat
Molecular function	Transducer
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	JAK-STAT cascade involved in growth hormone signaling pathway Traceable author statement. Source: Reactome 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: Compara mammary gland development Inferred from electronic annotation. Source: Compara 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 cascade Inferred from direct assay PubMed 7782332. Source: BHF-UCL positive regulation of cell migration Inferred from electronic annotation. Source: Compara 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 in response to insulin stimulus Inferred from direct assay PubMed 7493946. 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: Compara positive regulation of phosphatidylinositol 3-kinase activity Inferred from sequence or structural similarity. Source: BHF-UCL protein kinase B signaling cascade Inferred from electronic annotation. Source: Compara protein localization to nucleus Inferred from electronic annotation. Source: Compara regulation of gene expression Inferred from electronic annotation. Source: Compara
Cellular_component	caveola Inferred from direct assay PubMed 15182363. Source: BHF-UCL cytosol Traceable author statement. Source: Reactome insulin receptor complex Inferred from sequence or structural similarity. Source: BHF-UCL nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	SH2 domain binding Inferred from sequence or structural similarity. Source: UniProtKB phosphatidylinositol 3-kinase binding Inferred from sequence or structural similarity. Source: UniProtKB phospholipid binding Inferred from electronic annotation. Source: InterPro 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 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

PH

Domain

160 – 264

105

IRS-type PTB

Region

3 – 137

135

Mediates interaction with PHIP By similarity

Region

896 – 898

3

GRB2-binding By similarity

Motif

465 – 468

4

YXXM motif 1

Motif

551 – 554

4

YXXM motif 2

Motif

612 – 615

4

YXXM motif 3

Motif

632 – 635

4

YXXM motif 4

Motif

662 – 665

4

YXXM motif 5

Motif

732 – 735

4

YXXM motif 6

Motif

941 – 944

4

YXXM motif 7

Motif

989 – 992

4

YXXM motif 8

Motif

1012 – 1015

4

YXXM motif 9

Compositional bias

128 – 134

7

Poly-Gly

Compositional bias

268 – 444

177

Ser-rich

Compositional bias

680 – 686

7

Poly-Ser

Compositional bias

807 – 815

9

Poly-Ser

Compositional bias

877 – 882

6

Poly-Gln

Compositional bias

1192 – 1210

19

Pro-rich

Amino acid modifications

Modified residue

3

1

Phosphoserine By similarity

Modified residue

99

1

Phosphoserine; by CK2 By similarity

Modified residue

270

1

Phosphoserine; by RPS6KB1 Ref.15

Modified residue

307

1

Phosphoserine; by RPS6KB1 Ref.15

Modified residue

312

1

Phosphoserine; by IKKB and MAPK8

Modified residue

329

1

Phosphoserine By similarity

Modified residue

345

1

Phosphoserine By similarity

Modified residue

348

1

Phosphoserine Ref.18

Modified residue

465

1

Phosphotyrosine; by INSR By similarity

Modified residue

612

1

Phosphotyrosine; by INSR

Modified residue

629

1

Phosphoserine Ref.13

Modified residue

632

1

Phosphotyrosine; by INSR

Modified residue

636

1

Phosphoserine Ref.13 Ref.15

Modified residue

662

1

Phosphotyrosine Ref.12

Modified residue

794

1

Phosphoserine; by AMPK and SIK2 Ref.8

Modified residue

896

1

Phosphotyrosine; by INSR By similarity

Modified residue

941

1

Phosphotyrosine; by INSR

Modified residue

989

1

Phosphotyrosine; by INSR By similarity

Modified residue

1101

1

Phosphoserine; by RPS6KB1 and PKC/PRKCQ Ref.9 Ref.15

Modified residue

1145

1

Phosphoserine By similarity

Modified residue

1179

1

Phosphotyrosine; by INSR By similarity

Modified residue

1223

1

Phosphoserine By similarity

Modified residue

1229

1

Phosphotyrosine; by INSR By similarity

Natural variations

Natural variant

158

1

P → R.
Corresponds to variant rs1801108 [ dbSNP | Ensembl ].

VAR_014853

Natural variant

209

1

M → T.
Corresponds to variant rs1801118 [ dbSNP | Ensembl ].

VAR_014854

Natural variant

512

1

A → P. Ref.23
Corresponds to variant rs1801276 [ dbSNP | Ensembl ].

VAR_005299

Natural variant

608

1

T → R May contribute to insulin resistance by impairing metabolic signaling through PI3K-dependent pathways. Ref.29

VAR_025320

Natural variant

723

1

Missing in NIDDM. Ref.24

VAR_005301

Natural variant

809

1

S → F.
Corresponds to variant rs1801120 [ dbSNP | Ensembl ].

VAR_014855

Natural variant

892

1

S → G.
Corresponds to variant rs1801277 [ dbSNP | Ensembl ].

VAR_014856

Natural variant

971

1

G → R. Ref.23 Ref.26 Ref.27 Ref.28 Ref.30 Ref.31
Corresponds to variant rs1801278 [ dbSNP | Ensembl ].

VAR_005300

Natural variant

1043

1

S → Y in NIDDM. Ref.25

VAR_005302

Natural variant

1095

1

C → Y in NIDDM. Ref.25

VAR_005303

Natural variant

1137

1

D → N.
Corresponds to variant rs3731594 [ dbSNP | Ensembl ].

VAR_021837

Experimental info

Mutagenesis

794

1

S → A: Loss of phosphorylation by SIK2. Ref.8

Sequence conflict

134

1

G → GG in AAB21608. Ref.2

Sequence conflict

362

1

S → R in AAB21608. Ref.2

Sequence conflict

384

1

P → R in AAB21608. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

1242

Helix Strand Turn

Details...

Beta strand

13 – 20

8

Turn

22 – 24

3

Beta strand

27 – 33

7

Turn

37 – 39

3

Beta strand

40 – 49

10

Helix

50 – 54

5

Beta strand

61 – 65

5

Helix

66 – 68

3

Beta strand

69 – 75

7

Beta strand

81 – 90

10

Beta strand

92 – 96

5

Helix

100 – 113

14

Beta strand

161 – 172

12

Helix

173 – 176

4

Beta strand

181 – 187

7

Beta strand

189 – 196

8

Beta strand

203 – 207

5

Helix

208 – 210

3

Beta strand

211 – 217

7

Beta strand

220 – 225

6

Beta strand

233 – 239

7

Helix

243 – 258

16

Helix

259 – 261

3

Beta strand

897 – 901

5

Sequences

	Sequence		Length	Mass (Da)
	P35568 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: 3C0EFD9E32B3E64A	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

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] [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, MASS SPECTROMETRY.
[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, MASS SPECTROMETRY. 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, MASS SPECTROMETRY. 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 AND 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.

IPI

IPI00019471.

PIR

JS0670. I53160.

RefSeq

NP_005535.1. NM_005544.2.

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	[»]

ProteinModelPortal

P35568.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-523N.

IntAct

P35568. 8 interactions.

MINT

MINT-149537.

STRING

9606.ENSP00000304895.

PTM databases

PhosphoSite

P35568.

Polymorphism databases

DMDM

547738.

Proteomic databases

PaxDb

P35568.

PRIDE

P35568.

Protocols and materials databases

DNASU

3667.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000305123; ENSP00000304895; ENSG00000169047.

GeneID

3667.

KEGG

hsa:3667.

UCSC

uc002voh.4. human.

Organism-specific databases

CTD

3667.

GeneCards

GC02M227563.

HGNC

HGNC:6125. IRS1.

HPA

CAB005261.

MIM

125853. phenotype.
147545. gene.

neXtProt

NX_P35568.

PharmGKB

PA203.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG81285.

HOGENOM

HOG000113103.

HOVERGEN

HBG000542.

InParanoid

P35568.

KO

K16172.

OMA

EYTEMMP.

OrthoDB

EOG4J6RQG.

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_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

SignaLink

P35568.

Gene expression databases

Bgee

P35568.

CleanEx

HS_IRS1.

Genevestigator

P35568.

GermOnline

ENSG00000169047. Homo sapiens.

Family and domain databases

Gene3D

2.30.29.30. 2 hits.

InterPro

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

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

EvolutionaryTrace

P35568.

GenomeRNAi

3667.

NextBio

14355.

PMAP-CutDB

P35568.

SOURCE

Search...

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:	May 29, 2013
This is version 149 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.