UniProtKB - O14654 (IRS4_HUMAN)
Protein
Insulin receptor substrate 4
Gene
IRS4
Organism
Homo sapiens (Human)
Status
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
GO - Biological processi
- insulin receptor signaling pathway Source: GO_Central
- signal transduction Source: ProtInc
Keywordsi
Molecular function | Transducer |
Enzyme and pathway databases
PathwayCommonsi | O14654 |
Reactomei | R-HSA-2428928, IRS-related events triggered by IGF1R |
SignaLinki | O14654 |
SIGNORi | O14654 |
Names & Taxonomyi
Protein namesi | Recommended name: Insulin receptor substrate 4Short name: IRS-4 Alternative name(s): 160 kDa phosphotyrosine protein Short name: py160 Phosphoprotein of 160 kDa Short name: pp160 |
Gene namesi | Name:IRS4 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
EuPathDBi | HostDB:ENSG00000133124.11 |
HGNCi | HGNC:6128, IRS4 |
MIMi | 300904, gene |
neXtProti | NX_O14654 |
Subcellular locationi
Plasma membrane
- Cell membrane 1 Publication; Peripheral membrane protein 1 Publication; Cytoplasmic side 1 Publication
Cytosol
- cytosol Source: GO_Central
Plasma Membrane
- plasma membrane Source: GO_Central
Keywords - Cellular componenti
Cell membrane, MembranePathology & Biotechi
Involvement in diseasei
Hypothyroidism, congenital, non-goitrous, 9 (CHNG9)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of central hypothyroidism, a disorder characterized by sub-optimal thyroid hormone secretion, due to insufficient stimulation by thyrotropin of an otherwise normal thyroid gland. It may be caused by congenital or acquired disorders of the pituitary gland or hypothalamus. CHNG9 is a congenital, X-linked recessive form. Patients have a small thyroid gland with low free T4 levels and inappropriately normal levels of thyrotropin.
Related information in OMIMFeature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_083291 | 215 – 1257 | Missing in CHNG9. 1 PublicationAdd BLAST | 1043 |
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 700 | Y → 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 Publication | 1 | |
Mutagenesisi | 717 | Y → 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 Publication | 1 | |
Mutagenesisi | 743 | Y → 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 Publication | 1 | |
Mutagenesisi | 779 | Y → 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 Publication | 1 |
Keywords - Diseasei
Congenital hypothyroidism, Disease mutationOrganism-specific databases
DisGeNETi | 8471 |
MalaCardsi | IRS4 |
MIMi | 301035, phenotype |
OpenTargetsi | ENSG00000133124 |
PharmGKBi | PA29923 |
Miscellaneous databases
Pharosi | O14654, Tbio |
Polymorphism and mutation databases
BioMutai | IRS4 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000314678 | 1 – 1257 | Insulin receptor substrate 4Add BLAST | 1257 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 921 | Phosphotyrosine1 Publication | 1 |
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
PhosphoproteinProteomic databases
MassIVEi | O14654 |
MaxQBi | O14654 |
PaxDbi | O14654 |
PeptideAtlasi | O14654 |
PRIDEi | O14654 |
ProteomicsDBi | 48151 |
PTM databases
iPTMneti | O14654 |
PhosphoSitePlusi | O14654 |
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
Bgeei | ENSG00000133124, Expressed in adenohypophysis and 32 other tissues |
Genevisiblei | O14654, HS |
Organism-specific databases
HPAi | ENSG00000133124, Tissue enriched (pituitary) |
Interactioni
Subunit structurei
Interacts with SOCS6 in response to stimulation 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 PublicationsBinary interactionsi
Hide detailsO14654
With | #Exp. | IntAct |
---|---|---|
CRK [P46108] | 8 | EBI-356594,EBI-886 |
EGFR [P00533] | 2 | EBI-356594,EBI-297353 |
PTGES3 [Q15185] | 2 | EBI-356594,EBI-1049387 |
GO - Molecular functioni
- insulin receptor binding Source: GO_Central
- phosphatidylinositol 3-kinase binding Source: GO_Central
Protein-protein interaction databases
BioGRIDi | 114048, 158 interactors |
IntActi | O14654, 109 interactors |
MINTi | O14654 |
STRINGi | 9606.ENSP00000361202 |
Miscellaneous databases
RNActi | O14654, protein |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 78 – 199 | PHPROSITE-ProRule annotationAdd BLAST | 122 | |
Domaini | 231 – 335 | IRS-type PTBPROSITE-ProRule annotationAdd BLAST | 105 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 678 – 800 | CRK-bindingAdd BLAST | 123 | |
Regioni | 895 – 897 | GRB2-binding | 3 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 487 – 490 | YXXM motif 1 | 4 | |
Motifi | 700 – 703 | YXXM motif 2 | 4 | |
Motifi | 717 – 720 | YXXM motif 3 | 4 | |
Motifi | 743 – 746 | YXXM motif 4 | 4 | |
Motifi | 779 – 782 | YXXM motif 5 | 4 | |
Motifi | 828 – 831 | YXXM motif 6 | 4 | |
Motifi | 921 – 924 | YXXM motif 7 | 4 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 18 – 28 | Poly-AlaAdd BLAST | 11 | |
Compositional biasi | 124 – 137 | Ala-richAdd BLAST | 14 | |
Compositional biasi | 218 – 226 | Poly-Ala | 9 | |
Compositional biasi | 628 – 639 | Pro-richAdd BLAST | 12 | |
Compositional biasi | 1094 – 1212 | Ala-richAdd BLAST | 119 |
Keywords - Domaini
RepeatPhylogenomic databases
eggNOGi | ENOG502SD84, Eukaryota |
GeneTreei | ENSGT00940000160883 |
HOGENOMi | CLU_290952_0_0_1 |
InParanoidi | O14654 |
OMAi | EDSRGYM |
OrthoDBi | 298675at2759 |
PhylomeDBi | O14654 |
TreeFami | TF325994 |
Family and domain databases
CDDi | cd01204, PTB_IRS, 1 hit |
Gene3Di | 2.30.29.30, 2 hits |
InterProi | View protein in InterPro IPR039011, IRS IPR002404, IRS_PTB IPR011993, PH-like_dom_sf IPR001849, PH_domain |
PANTHERi | PTHR10614, PTHR10614, 1 hit |
Pfami | View protein in Pfam PF02174, IRS, 1 hit |
PRINTSi | PR00628, INSULINRSI |
SMARTi | View protein in SMART SM00233, PH, 1 hit SM00310, PTBI, 1 hit |
PROSITEi | View protein in PROSITE PS51064, IRS_PTB, 1 hit PS50003, PH_DOMAIN, 1 hit |
i Sequence
Sequence statusi: Complete.
O14654-1 [UniParc]FASTAAdd to basket
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
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_038042 | 20 | A → V in a colorectal cancer sample; somatic mutation. 1 Publication | 1 | |
Natural variantiVAR_051078 | 34 | L → F. Corresponds to variant dbSNP:rs1801162Ensembl. | 1 | |
Natural variantiVAR_083291 | 215 – 1257 | Missing in CHNG9. 1 PublicationAdd BLAST | 1043 | |
Natural variantiVAR_038043 | 215 | G → E in a colorectal cancer sample; somatic mutation. 1 Publication | 1 | |
Natural variantiVAR_051079 | 508 | N → K. Corresponds to variant dbSNP:rs34287560Ensembl. | 1 | |
Natural variantiVAR_038044 | 557 | G → R in a colorectal cancer sample; somatic mutation. 1 Publication | 1 | |
Natural variantiVAR_051080 | 879 | H → D. Corresponds to variant dbSNP:rs1801164Ensembl. | 1 | |
Natural variantiVAR_061669 | 1230 | D → Y. Corresponds to variant dbSNP:rs28546943EnsemblClinVar. | 1 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AF007567 mRNA Translation: AAC51738.1 AL035425 Genomic DNA No translation available. CH471120 Genomic DNA Translation: EAX02682.1 |
CCDSi | CCDS14544.1 |
RefSeqi | NP_003595.1, NM_003604.2 |
Genome annotation databases
Ensembli | ENST00000372129; ENSP00000361202; ENSG00000133124 |
GeneIDi | 8471 |
KEGGi | hsa:8471 |
UCSCi | uc004eoc.3, human |
Keywords - Coding sequence diversityi
PolymorphismSimilar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AF007567 mRNA Translation: AAC51738.1 AL035425 Genomic DNA No translation available. CH471120 Genomic DNA Translation: EAX02682.1 |
CCDSi | CCDS14544.1 |
RefSeqi | NP_003595.1, NM_003604.2 |
3D structure databases
SMRi | O14654 |
ModBasei | Search... |
Protein-protein interaction databases
BioGRIDi | 114048, 158 interactors |
IntActi | O14654, 109 interactors |
MINTi | O14654 |
STRINGi | 9606.ENSP00000361202 |
PTM databases
iPTMneti | O14654 |
PhosphoSitePlusi | O14654 |
Polymorphism and mutation databases
BioMutai | IRS4 |
Proteomic databases
MassIVEi | O14654 |
MaxQBi | O14654 |
PaxDbi | O14654 |
PeptideAtlasi | O14654 |
PRIDEi | O14654 |
ProteomicsDBi | 48151 |
Protocols and materials databases
Antibodypediai | 15310, 164 antibodies |
DNASUi | 8471 |
Genome annotation databases
Ensembli | ENST00000372129; ENSP00000361202; ENSG00000133124 |
GeneIDi | 8471 |
KEGGi | hsa:8471 |
UCSCi | uc004eoc.3, human |
Organism-specific databases
CTDi | 8471 |
DisGeNETi | 8471 |
EuPathDBi | HostDB:ENSG00000133124.11 |
GeneCardsi | IRS4 |
HGNCi | HGNC:6128, IRS4 |
HPAi | ENSG00000133124, Tissue enriched (pituitary) |
MalaCardsi | IRS4 |
MIMi | 300904, gene 301035, phenotype |
neXtProti | NX_O14654 |
OpenTargetsi | ENSG00000133124 |
PharmGKBi | PA29923 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | ENOG502SD84, Eukaryota |
GeneTreei | ENSGT00940000160883 |
HOGENOMi | CLU_290952_0_0_1 |
InParanoidi | O14654 |
OMAi | EDSRGYM |
OrthoDBi | 298675at2759 |
PhylomeDBi | O14654 |
TreeFami | TF325994 |
Enzyme and pathway databases
PathwayCommonsi | O14654 |
Reactomei | R-HSA-2428928, IRS-related events triggered by IGF1R |
SignaLinki | O14654 |
SIGNORi | O14654 |
Miscellaneous databases
BioGRID-ORCSi | 8471, 8 hits in 472 CRISPR screens |
GeneWikii | IRS4 |
GenomeRNAii | 8471 |
Pharosi | O14654, Tbio |
PROi | PR:O14654 |
RNActi | O14654, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000133124, Expressed in adenohypophysis and 32 other tissues |
Genevisiblei | O14654, HS |
Family and domain databases
CDDi | cd01204, PTB_IRS, 1 hit |
Gene3Di | 2.30.29.30, 2 hits |
InterProi | View protein in InterPro IPR039011, IRS IPR002404, IRS_PTB IPR011993, PH-like_dom_sf IPR001849, PH_domain |
PANTHERi | PTHR10614, PTHR10614, 1 hit |
Pfami | View protein in Pfam PF02174, IRS, 1 hit |
PRINTSi | PR00628, INSULINRSI |
SMARTi | View protein in SMART SM00233, PH, 1 hit SM00310, PTBI, 1 hit |
PROSITEi | View protein in PROSITE PS51064, IRS_PTB, 1 hit PS50003, PH_DOMAIN, 1 hit |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | IRS4_HUMAN | |
Accessioni | O14654Primary (citable) accession number: O14654 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | January 15, 2008 |
Last sequence update: | January 1, 1998 | |
Last modified: | December 2, 2020 | |
This is version 175 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | 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. |
Miscellaneousi
Keywords - Technical termi
Direct protein sequencing, Reference proteomeDocuments
- Human polymorphisms and disease mutations
Index of human polymorphisms and disease mutations - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - Human chromosome X
Human chromosome X: entries, gene names and cross-references to MIM - Human entries with polymorphisms or disease mutations
List of human entries with polymorphisms or disease mutations