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Protein

Insulin receptor substrate 4

Gene

IRS4

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

Functioni

Acts as an interface between multiple growth factor receptors possessing tyrosine kinase activity, such as insulin receptor, IGF1R and FGFR1, and a complex network of intracellular signaling molecules containing SH2 domains. Involved in the IGF1R mitogenic signaling pathway. Promotes the AKT1 signaling pathway and BAD phosphorylation during insulin stimulation without activation of RPS6KB1 or the inhibition of apoptosis. Interaction with GRB2 enhances insulin-stimulated mitogen-activated protein kinase activity. May be involved in nonreceptor tyrosine kinase signaling in myoblasts. Plays a pivotal role in the proliferation/differentiation of hepatoblastoma cell through EPHB2 activation upon IGF1 stimulation. May play a role in the signal transduction in response to insulin and to a lesser extent in response to IL4 and GH on mitogenesis. Plays a role in growth, reproduction and glucose homeostasis. May act as negative regulators of the IGF1 signaling pathway by suppressing the function of IRS1 and IRS2.5 Publications

GO - Molecular functioni

  • insulin receptor binding Source: GO_Central
  • phosphatidylinositol 3-kinase binding Source: GO_Central
  • SH3/SH2 adaptor activity Source: ProtInc
  • signal transducer activity Source: ProtInc

GO - Biological processi

  • insulin receptor signaling pathway Source: GO_Central
  • regulation of lipid metabolic process Source: GO_Central
  • signal transduction Source: ProtInc
Complete GO annotation...

Keywords - Molecular functioni

Transducer

Enzyme and pathway databases

BioCyciZFISH:ENSG00000126685-MONOMER.
ReactomeiR-HSA-2428928. IRS-related events triggered by IGF1R.
SignaLinkiO14654.
SIGNORiO14654.

Names & Taxonomyi

Protein namesi
Recommended name:
Insulin receptor substrate 4
Short name:
IRS-4
Alternative name(s):
160 kDa phosphotyrosine protein
Short name:
py160
Phosphoprotein of 160 kDa
Short name:
pp160
Gene namesi
Name:IRS4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

HGNCiHGNC:6128. IRS4.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi700Y → F: No effect. Reduces interaction with CRK by 50%; when associated with F-717. Abolishes interaction with CRK; when associated with F-717; F-743 and F-779. 1 Publication1
Mutagenesisi717Y → F: No effect. Reduces interaction with CRK by 50%; when associated with F-700. Abolishes interaction with CRK; when associated with F-700; F-743 and F-779. 1 Publication1
Mutagenesisi743Y → F: No effect. Reduces interaction with CRK by 50%; when associated with F-779. Abolishes interaction with CRK; when associated with F-700; F-717 and F-779. 1 Publication1
Mutagenesisi779Y → F: No effect. Reduces interaction with CRK by 50%; when associated with F-743. Abolishes interaction with CRK; when associated with F-700; F-717 and F-743. 1 Publication1

Organism-specific databases

DisGeNETi8471.
OpenTargetsiENSG00000133124.
PharmGKBiPA29923.

Polymorphism and mutation databases

BioMutaiIRS4.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003146781 – 1257Insulin receptor substrate 4Add BLAST1257

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei921Phosphotyrosine1 Publication1

Post-translational modificationi

Phosphorylated on tyrosine residues in response to both insulin and IGF1 signaling. Phosphorylated on Tyr-921 in response to FGF2 signaling. Phosphorylation of Tyr-921 is required for GRB2, phospholipase C-gamma and phosphatidylinositol 3-kinase interaction.3 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiO14654.
PaxDbiO14654.
PeptideAtlasiO14654.
PRIDEiO14654.

PTM databases

iPTMnetiO14654.
PhosphoSitePlusiO14654.

Expressioni

Tissue specificityi

Expressed in myoblasts. Expressed in liver and hepatocellular carcinoma.2 Publications

Inductioni

Down-regulated by PPP4C in a phosphatase activity-dependent manner.1 Publication

Gene expression databases

BgeeiENSG00000133124.
CleanExiHS_IRS4.
GenevisibleiO14654. HS.

Organism-specific databases

HPAiHPA017372.

Interactioni

Subunit structurei

Interacts with SOCS6 in response to stimulatiom with either insulin or IGF1 (By similarity). Interacts with CRK and CRKL. Interaction with CRK is stronger than with CRKL. Interacts with CRK via the phosphorylated YXXM motifs. Interacts with GRB2 and PIK3R1. Interacts with PLC-gamma, SHC1, PTK6, PPP4C and NISCH.By similarity8 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CRKP461088EBI-356594,EBI-886
EGFRP005332EBI-356594,EBI-297353
PTGES3Q151852EBI-356594,EBI-1049387

GO - Molecular functioni

  • insulin receptor binding Source: GO_Central
  • phosphatidylinositol 3-kinase binding Source: GO_Central
  • SH3/SH2 adaptor activity Source: ProtInc

Protein-protein interaction databases

BioGridi114048. 96 interactors.
IntActiO14654. 90 interactors.
MINTiMINT-1151881.
STRINGi9606.ENSP00000361202.

Structurei

3D structure databases

ProteinModelPortaliO14654.
SMRiO14654.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini78 – 199PHPROSITE-ProRule annotationAdd BLAST122
Domaini231 – 335IRS-type PTBPROSITE-ProRule annotationAdd BLAST105

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni678 – 800CRK-bindingAdd BLAST123
Regioni895 – 897GRB2-binding3

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi487 – 490YXXM motif 14
Motifi700 – 703YXXM motif 24
Motifi717 – 720YXXM motif 34
Motifi743 – 746YXXM motif 44
Motifi779 – 782YXXM motif 54
Motifi828 – 831YXXM motif 64
Motifi921 – 924YXXM motif 74

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi18 – 28Poly-AlaAdd BLAST11
Compositional biasi124 – 137Ala-richAdd BLAST14
Compositional biasi218 – 226Poly-Ala9
Compositional biasi628 – 639Pro-richAdd BLAST12
Compositional biasi1094 – 1212Ala-richAdd BLAST119

Sequence similaritiesi

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

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiENOG410IXEK. Eukaryota.
ENOG410Z9EP. LUCA.
GeneTreeiENSGT00530000063420.
HOGENOMiHOG000113104.
HOVERGENiHBG107140.
InParanoidiO14654.
KOiK17446.
OMAiAFSNYVN.
OrthoDBiEOG091G02EF.
PhylomeDBiO14654.
TreeFamiTF325994.

Family and domain databases

CDDicd01204. PTB_IRS. 1 hit.
Gene3Di2.30.29.30. 2 hits.
InterProiIPR002404. IRS_PTB.
IPR011993. PH_dom-like.
IPR001849. PH_domain.
[Graphical view]
PfamiPF02174. IRS. 1 hit.
[Graphical view]
PRINTSiPR00628. INSULINRSI.
SMARTiSM00233. PH. 1 hit.
SM00310. PTBI. 1 hit.
[Graphical view]
SUPFAMiSSF50729. SSF50729. 2 hits.
PROSITEiPS51064. IRS_PTB. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O14654-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MASCSFTRDQ ATRRLRGAAA AAAAALAAVV TTPLLSSGTP TALIGTGSSC
60 70 80 90 100
PGAMWLSTAT GSRSDSESEE EDLPVGEEVC KRGYLRKQKH GHRRYFVLKL
110 120 130 140 150
ETADAPARLE YYENARKFRH SVRAAAAAAA AAASGAAIPP LIPPRRVITL
160 170 180 190 200
YQCFSVSQRA DARYRHLIAL FTQDEYFAMV AENESEQESW YLLLSRLILE
210 220 230 240 250
SKRRRCGTLG AQPDGEPAAL AAAAAAEPPF YKDVWQVIVK PRGLGHRKEL
260 270 280 290 300
SGVFRLCLTD EEVVFVRLNT EVASVVVQLL SIRRCGHSEQ YFFLEVGRST
310 320 330 340 350
VIGPGELWMQ VDDCVVAQNM HELFLEKMRA LCADEYRARC RSYSISIGAH
360 370 380 390 400
LLTLLSARRH LGLVPLEPGG WLRRSRFEQF CHLRAIGDGE DEMLFTRRFV
410 420 430 440 450
TPSEPVAHSR RGRLHLPRGR RSRRAVSVPA SFFRRLAPSP ARPRHPAEAP
460 470 480 490 500
NNGARLSSEV SGSGSGNFGE EGNPQGKEDQ EGSGGDYMPM NNWGSGNGRG
510 520 530 540 550
SGGGQGSNGQ GSSSHSSGGN QCSGEGQGSR GGQGSNGQGS GGNQCSRDGQ
560 570 580 590 600
GTAGGHGSGG GQRPGGGHGS GGGQGPGDGH GSGGGKNSGG GKGSGSGKGS
610 620 630 640 650
DGDGERGKSL KKRSYFGKLT QSKQQQMPPP PPPPPPPPPA GGTGGKGKSG
660 670 680 690 700
GRFRLYFCVD RGATKECKEA KEVKDAEIPE GAARGPHRAR AFDEDEDDPY
710 720 730 740 750
VPMRPGVATP LVSSSDYMPM APQNVSASKK RHSRSPFEDS RGYMMMFPRV
760 770 780 790 800
SPPPAPSPPK APDTNKEDDS KDNDSESDYM FMAPGAGAIP KNPRNPQGGS
810 820 830 840 850
SSKSWSSYFS LPNPFRSSPL GQNDNSEYVP MLPGKFLGRG LDKEVSYNWD
860 870 880 890 900
PKDAASKPSG EGSFSKPGDG GSPSKPSDHE PPKNKAKRPN RLSFITKGYK
910 920 930 940 950
IKPKPQKPTH EQREADSSSD YVNMDFTKRE SNTPAPSTQG LPDSWGIIAE
960 970 980 990 1000
PRQSAFSNYV NVEFGVPFPN PANDLSDLLR AIPRANPLSL DSARWPLPPL
1010 1020 1030 1040 1050
PLSATGSNAI EEEGDYIEVI FNSAMTPAMA LADSAIRYDA ETGRIYVVDP
1060 1070 1080 1090 1100
FSECCMDISL SPSRCSEPPP VARLLQEEEQ ERRRPQSRSQ SFFAAARAAV
1110 1120 1130 1140 1150
SAFPTDSLER DLSPSSAPAV ASAAEPTLAL SQVVAAASAL AAAPGIGAAA
1160 1170 1180 1190 1200
AAAGFDSASA RWFQPVANAA DAEAVRGAQD VAGGSNPGAH NPSANLARGD
1210 1220 1230 1240 1250
NQAGGAAAAA AAPEPPPRSR RVPRPPERED SDNDDDTHVR MDFARRDNQF

DSPKRGR
Length:1,257
Mass (Da):133,768
Last modified:January 1, 1998 - v1
Checksum:i4D512D65A7A80374
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03804220A → V in a colorectal cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_05107834L → F.Corresponds to variant rs1801162dbSNPEnsembl.1
Natural variantiVAR_038043215G → E in a colorectal cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_051079508N → K.Corresponds to variant rs34287560dbSNPEnsembl.1
Natural variantiVAR_038044557G → R in a colorectal cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_051080879H → D.Corresponds to variant rs1801164dbSNPEnsembl.1
Natural variantiVAR_0616691230D → Y.Corresponds to variant rs28546943dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF007567 mRNA. Translation: AAC51738.1.
AL035425 Genomic DNA. Translation: CAB90290.1.
CH471120 Genomic DNA. Translation: EAX02682.1.
CCDSiCCDS14544.1.
RefSeqiNP_003595.1. NM_003604.2.
UniGeneiHs.407141.
Hs.460872.

Genome annotation databases

EnsembliENST00000372129; ENSP00000361202; ENSG00000133124.
GeneIDi8471.
KEGGihsa:8471.
UCSCiuc004eoc.3. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF007567 mRNA. Translation: AAC51738.1.
AL035425 Genomic DNA. Translation: CAB90290.1.
CH471120 Genomic DNA. Translation: EAX02682.1.
CCDSiCCDS14544.1.
RefSeqiNP_003595.1. NM_003604.2.
UniGeneiHs.407141.
Hs.460872.

3D structure databases

ProteinModelPortaliO14654.
SMRiO14654.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114048. 96 interactors.
IntActiO14654. 90 interactors.
MINTiMINT-1151881.
STRINGi9606.ENSP00000361202.

PTM databases

iPTMnetiO14654.
PhosphoSitePlusiO14654.

Polymorphism and mutation databases

BioMutaiIRS4.

Proteomic databases

MaxQBiO14654.
PaxDbiO14654.
PeptideAtlasiO14654.
PRIDEiO14654.

Protocols and materials databases

DNASUi8471.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000372129; ENSP00000361202; ENSG00000133124.
GeneIDi8471.
KEGGihsa:8471.
UCSCiuc004eoc.3. human.

Organism-specific databases

CTDi8471.
DisGeNETi8471.
GeneCardsiIRS4.
HGNCiHGNC:6128. IRS4.
HPAiHPA017372.
MIMi300904. gene.
neXtProtiNX_O14654.
OpenTargetsiENSG00000133124.
PharmGKBiPA29923.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IXEK. Eukaryota.
ENOG410Z9EP. LUCA.
GeneTreeiENSGT00530000063420.
HOGENOMiHOG000113104.
HOVERGENiHBG107140.
InParanoidiO14654.
KOiK17446.
OMAiAFSNYVN.
OrthoDBiEOG091G02EF.
PhylomeDBiO14654.
TreeFamiTF325994.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000126685-MONOMER.
ReactomeiR-HSA-2428928. IRS-related events triggered by IGF1R.
SignaLinkiO14654.
SIGNORiO14654.

Miscellaneous databases

GeneWikiiIRS4.
GenomeRNAii8471.
PROiO14654.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000133124.
CleanExiHS_IRS4.
GenevisibleiO14654. HS.

Family and domain databases

CDDicd01204. PTB_IRS. 1 hit.
Gene3Di2.30.29.30. 2 hits.
InterProiIPR002404. IRS_PTB.
IPR011993. PH_dom-like.
IPR001849. PH_domain.
[Graphical view]
PfamiPF02174. IRS. 1 hit.
[Graphical view]
PRINTSiPR00628. INSULINRSI.
SMARTiSM00233. PH. 1 hit.
SM00310. PTBI. 1 hit.
[Graphical view]
SUPFAMiSSF50729. SSF50729. 2 hits.
PROSITEiPS51064. IRS_PTB. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiIRS4_HUMAN
AccessioniPrimary (citable) accession number: O14654
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 15, 2008
Last sequence update: January 1, 1998
Last modified: November 30, 2016
This is version 141 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

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome X
    Human chromosome X: 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. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.