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P35568

- IRS1_HUMAN

UniProt

P35568 - IRS1_HUMAN

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Protein

Insulin receptor substrate 1

Gene

IRS1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

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 kinase C binding Source: BHF-UCL
  5. SH2 domain binding Source: UniProtKB
  6. signal transducer activity Source: ProtInc
  7. 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
Complete GO annotation...

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. ciliary basal body Source: Ensembl
  3. cytoplasm Source: UniProtKB
  4. cytosol Source: Reactome
  5. insulin receptor complex Source: BHF-UCL
  6. intracellular membrane-bounded organelle Source: UniProtKB
  7. nucleus Source: UniProtKB
  8. plasma membrane Source: Reactome
Complete GO annotation...

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 RPS6KB11 Publication
Modified residuei307 – 3071Phosphoserine; by RPS6KB12 Publications
Modified residuei312 – 3121Phosphoserine; by IKKB, MAPK8 and RPS6KB12 Publications
Modified residuei345 – 3451PhosphoserineBy similarity
Modified residuei348 – 3481Phosphoserine1 Publication
Modified residuei465 – 4651Phosphotyrosine; by INSRBy similarity
Modified residuei527 – 5271Phosphoserine; by RPS6KB11 Publication
Modified residuei612 – 6121Phosphotyrosine; by INSR1 Publication
Modified residuei629 – 6291Phosphoserine1 Publication
Modified residuei632 – 6321Phosphotyrosine; by INSR1 Publication
Modified residuei636 – 6361Phosphoserine; by RPS6KB13 Publications
Modified residuei662 – 6621Phosphotyrosine1 Publication
Modified residuei794 – 7941Phosphoserine; by AMPK and SIK21 Publication
Modified residuei896 – 8961Phosphotyrosine; by INSRBy similarity
Modified residuei941 – 9411Phosphotyrosine; by INSR1 Publication
Modified residuei989 – 9891Phosphotyrosine; by INSRBy similarity
Modified residuei1101 – 11011Phosphoserine; by RPS6KB1 and PKC/PRKCQ2 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.
GeneTreeiENSGT00530000063420.
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

        10         20         30         40         50
MASPPESDGF SDVRKVGYLR KPKSMHKRFF VLRAASEAGG PARLEYYENE
60 70 80 90 100
KKWRHKSSAP KRSIPLESCF NINKRADSKN KHLVALYTRD EHFAIAADSE
110 120 130 140 150
AEQDSWYQAL LQLHNRAKGH HDGAAALGAG GGGGSCSGSS GLGEAGEDLS
160 170 180 190 200
YGDVPPGPAF KEVWQVILKP KGLGQTKNLI GIYRLCLTSK TISFVKLNSE
210 220 230 240 250
AAAVVLQLMN IRRCGHSENF FFIEVGRSAV TGPGEFWMQV DDSVVAQNMH
260 270 280 290 300
ETILEAMRAM SDEFRPRSKS QSSSNCSNPI SVPLRRHHLN NPPPSQVGLT
310 320 330 340 350
RRSRTESITA TSPASMVGGK PGSFRVRASS DGEGTMSRPA SVDGSPVSPS
360 370 380 390 400
TNRTHAHRHR GSARLHPPLN HSRSIPMPAS RCSPSATSPV SLSSSSTSGH
410 420 430 440 450
GSTSDCLFPR RSSASVSGSP SDGGFISSDE YGSSPCDFRS SFRSVTPDSL
460 470 480 490 500
GHTPPARGEE ELSNYICMGG KGPSTLTAPN GHYILSRGGN GHRCTPGTGL
510 520 530 540 550
GTSPALAGDE AASAADLDNR FRKRTHSAGT SPTITHQKTP SQSSVASIEE
560 570 580 590 600
YTEMMPAYPP GGGSGGRLPG HRHSAFVPTR SYPEEGLEMH PLERRGGHHR
610 620 630 640 650
PDSSTLHTDD GYMPMSPGVA PVPSGRKGSG DYMPMSPKSV SAPQQIINPI
660 670 680 690 700
RRHPQRVDPN GYMMMSPSGG CSPDIGGGPS SSSSSSNAVP SGTSYGKLWT
710 720 730 740 750
NGVGGHHSHV LPHPKPPVES SGGKLLPCTG DYMNMSPVGD SNTSSPSDCY
760 770 780 790 800
YGPEDPQHKP VLSYYSLPRS FKHTQRPGEP EEGARHQHLR LSTSSGRLLY
810 820 830 840 850
AATADDSSSS TSSDSLGGGY CGARLEPSLP HPHHQVLQPH LPRKVDTAAQ
860 870 880 890 900
TNSRLARPTR LSLGDPKAST LPRAREQQQQ QQPLLHPPEP KSPGEYVNIE
910 920 930 940 950
FGSDQSGYLS GPVAFHSSPS VRCPSQLQPA PREEETGTEE YMKMDLGPGR
960 970 980 990 1000
RAAWQESTGV EMGRLGPAPP GAASICRPTR AVPSSRGDYM TMQMSCPRQS
1010 1020 1030 1040 1050
YVDTSPAAPV SYADMRTGIA AEEVSLPRAT MAAASSSSAA SASPTGPQGA
1060 1070 1080 1090 1100
AELAAHSSLL GGPQGPGGMS AFTRVNLSPN RNQSAKVIRA DPQGCRRRHS
1110 1120 1130 1140 1150
SETFSSTPSA TRVGNTVPFG AGAAVGGGGG SSSSSEDVKR HSSASFENVW
1160 1170 1180 1190 1200
LRPGELGGAP KEPAKLCGAA GGLENGLNYI DLDLVKDFKQ CPQECTPEPQ
1210 1220 1230 1240
PPPPPPPHQP LGSGESSSTR RSSEDLSAYA SISFQKQPED RQ
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.
GeneTreei ENSGT00530000063420.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 163 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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