IRS4 encodes the insulin receptor substrate 4, a cytoplasmic protein that contains many potential tyrosine and serine/threonine phosphorylation sites. Tyrosine-phosphorylated IRS4 protein has been shown to associate with cytoplasmic signalling molecules that contain SH2 domains. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation... See more...

Aliases for IRS4 Gene

Aliases for IRS4 Gene

  • Insulin Receptor Substrate 4 2 3 4 5
  • IRS-4 2 3 4
  • 160 KDa Phosphotyrosine Protein 3 4
  • Phosphoprotein Of 160 KDa 3 4
  • PY160 2 3
  • Pp160 3 4
  • CHNG9 3
  • Py160 4
  • IRS4 5

External Ids for IRS4 Gene

Previous GeneCards Identifiers for IRS4 Gene

  • GC0XM103383
  • GC0XM105051
  • GC0XM106008
  • GC0XM106747
  • GC0XM106171
  • GC0XM107781
  • GC0XM107862
  • GC0XM107975
  • GC0XM097599

Summaries for IRS4 Gene

Entrez Gene Summary for IRS4 Gene

  • IRS4 encodes the insulin receptor substrate 4, a cytoplasmic protein that contains many potential tyrosine and serine/threonine phosphorylation sites. Tyrosine-phosphorylated IRS4 protein has been shown to associate with cytoplasmic signalling molecules that contain SH2 domains. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation.. [provided by RefSeq, Jul 2008]

GeneCards Summary for IRS4 Gene

IRS4 (Insulin Receptor Substrate 4) is a Protein Coding gene. Diseases associated with IRS4 include Hypothyroidism, Congenital, Nongoitrous, 9 and Hypothyroidism. Among its related pathways are Signaling by GPCR and cGMP-PKG signaling pathway. Gene Ontology (GO) annotations related to this gene include obsolete signal transducer activity and insulin receptor binding. An important paralog of this gene is IRS2.

UniProtKB/Swiss-Prot Summary for IRS4 Gene

  • 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.

Gene Wiki entry for IRS4 Gene

No data available for CIViC Summary , Tocris Summary , PharmGKB "VIP" Summary , Rfam classification and piRNA Summary for IRS4 Gene

Genomics for IRS4 Gene

GeneHancer (GH) Regulatory Elements Pubs

Promoters and enhancers for IRS4 Gene
GeneHancer (GH) Identifier GH Type GH
Score
GH Sources Gene Association Score Total Score TSS distance (kb) Number of Genes Away Size (kb) Transcription Factor
Binding Sites
Gene Targets
GH0XJ108735 Promoter/Enhancer 1.5 Ensembl ENCODE CraniofacialAtlas 250.7 -0.1 -117 3 ZNF600 POLR2A ZIC2 FEZF1 ZNF341 SIN3A KLF9 SP2 KLF16 CTCF ENSG00000237863 IRS4 LOC101928358 lnc-IRS4-1 GUCY2F
GH0XJ108731 Promoter 0.7 Ensembl 0.7 +3.8 3783 0.8 ZNF600 SIN3A SCRT1 EZH2 CBX8 ZBTB17 ZBTB20 ZNF335 SCRT2 ENSG00000237863 IRS4 HSALNG0139477 COL4A5
GH0XJ108724 Enhancer 0.3 Ensembl 0.4 +11.3 11283 2.6 PRDM10 AL035425.3 HSALNG0139477 COL4A5 IRS4
GH0XJ108437 Promoter/Enhancer 1.9 EPDnew Ensembl ENCODE CraniofacialAtlas 0.1 +296.4 296383 7.6 IKZF1 ZNF600 ATF2 ZNF10 POLR2A CHD2 FEZF1 ZNF639 ZNF341 ZEB1 COL4A5 COL4A6 NONHSAG055082.2-001 lnc-COL4A6-2 piR-61945-542 IRS4
GH0XJ108717 Enhancer 0.3 Ensembl 0.4 +18.8 18783 0.4 ZBTB44 COL4A5 AL035425.3 IRS4 HSALNG0139474
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around IRS4 on the GeneHancer Hub at the UCSC Golden Path

Cistromic (ChIP-Seq) regulation report from SPP (The Signaling Pathways Project) for IRS4

Top Transcription factor binding sites by QIAGEN in the IRS4 gene promoter:
  • ARP-1
  • HOXA3
  • ITF-2
  • Lmo2
  • MIF-1
  • POU2F1
  • POU2F1a
  • Sp1
  • Tal-1beta
  • YY1

Genomic Locations for IRS4 Gene

Latest Assembly
chrX:108,719,946-108,736,584
(GRCh38/hg38)
Size:
16,639 bases
Orientation:
Minus strand

Previous Assembly
chrX:107,963,176-107,979,793
(GRCh37/hg19 by Entrez Gene)
Size:
16,618 bases
Orientation:
Minus strand

chrX:107,975,712-107,979,651
(GRCh37/hg19 by Ensembl)
Size:
3,940 bases
Orientation:
Minus strand

Genomic View for IRS4 Gene

Genes around IRS4 on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
IRS4 Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for IRS4 Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for IRS4 Gene

Proteins for IRS4 Gene

  • Protein details for IRS4 Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    O14654-IRS4_HUMAN
    Recommended name:
    Insulin receptor substrate 4
    Protein Accession:
    O14654

    Protein attributes for IRS4 Gene

    Size:
    1257 amino acids
    Molecular mass:
    133768 Da
    Quaternary structure:
    • 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.

neXtProt entry for IRS4 Gene

Post-translational modifications for IRS4 Gene

  • 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.
  • Ubiquitination at Lys240, Lys618, Lys803, Lys835, Lys843, and Lys928
  • Modification sites at PhosphoSitePlus

Other Protein References for IRS4 Gene

Antibodies for research

  • Abcam antibodies for IRS4

No data available for DME Specific Peptides for IRS4 Gene

Domains & Families for IRS4 Gene

Gene Families for IRS4 Gene

Human Protein Atlas (HPA):
  • Cancer-related genes
  • Predicted intracellular proteins

Protein Domains for IRS4 Gene

InterPro:
Blocks:
  • Pleckstrin-like
  • Insulin receptor substrate-1 PTB domain signature

Suggested Antigen Peptide Sequences for IRS4 Gene

GenScript: Design optimal peptide antigens:
  • Phosphoprotein of 160 kDa (IRS4_HUMAN)
genes like me logo Genes that share domains with IRS4: view

No data available for Graphical View of Domain Structure and UniProtKB/Swiss-Prot for IRS4 Gene

Function for IRS4 Gene

Molecular function for IRS4 Gene

UniProtKB/Swiss-Prot Function:
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.
UniProtKB/Swiss-Prot Induction:
Down-regulated by PPP4C in a phosphatase activity-dependent manner.

Phenotypes From GWAS Catalog for IRS4 Gene

Gene Ontology (GO) - Molecular Function for IRS4 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005158 insulin receptor binding IEA,IBA 21873635
GO:0005515 protein binding IPI 11316748
GO:0043548 phosphatidylinositol 3-kinase binding IBA 21873635
genes like me logo Genes that share ontologies with IRS4: view
genes like me logo Genes that share phenotypes with IRS4: view

Human Phenotype Ontology for IRS4 Gene

HPO Id HPO Name Alternative Ids Definition Synonyms

Inhibitory RNAs for research

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for IRS4

No data available for Enzyme Numbers (IUBMB) , Animal Models , Transcription Factor Targets and HOMER Transcription for IRS4 Gene

Localization for IRS4 Gene

Subcellular locations from UniProtKB/Swiss-Prot for IRS4 Gene

Cell membrane. Peripheral membrane protein. Cytoplasmic side.

Subcellular locations from

COMPARTMENTS
Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for IRS4 gene
Compartment Confidence
plasma membrane 4
cytosol 4
extracellular 2
nucleus 2
endoplasmic reticulum 2
cytoskeleton 1
mitochondrion 1
peroxisome 1
endosome 1
lysosome 1
golgi apparatus 1

Gene Ontology (GO) - Cellular Components for IRS4 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005829 cytosol IBA 21873635
GO:0005886 plasma membrane TAS --
GO:0016020 membrane IEA --
genes like me logo Genes that share ontologies with IRS4: view

No data available for Subcellular locations from the Human Protein Atlas (HPA) for IRS4 Gene

Pathways & Interactions for IRS4 Gene

genes like me logo Genes that share pathways with IRS4: view

Pathways by source for IRS4 Gene

1 GeneGo (Thomson Reuters) pathway for IRS4 Gene
  • Transcription Receptor-mediated HIF regulation
3 Qiagen pathways for IRS4 Gene
  • IGF1R Signaling
  • ILK Signaling
  • SOCS Pathway

SIGNOR curated interactions for IRS4 Gene

Is activated by:

Gene Ontology (GO) - Biological Process for IRS4 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0007165 signal transduction TAS 9261155
GO:0008286 insulin receptor signaling pathway IEA,IBA 21873635
genes like me logo Genes that share ontologies with IRS4: view

Drugs & Compounds for IRS4 Gene

(1) Drugs for IRS4 Gene - From: Novoseek

Name Status Disease Links Group Role Mechanism of Action Clinical Trials

(3) Additional Compounds for IRS4 Gene - From: Novoseek

Name Synonyms Role CAS Number PubChem IDs PubMed IDs
genes like me logo Genes that share compounds with IRS4: view

Transcripts for IRS4 Gene

mRNA/cDNA for IRS4 Gene

2 REFSEQ mRNAs :
2 NCBI additional mRNA sequence :
2 Ensembl transcripts including schematic representations, and UCSC links to gene/alias where relevant :

Inhibitory RNAs for research

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for IRS4

Alternative Splicing Database (ASD) splice patterns (SP) for IRS4 Gene

No ASD Table

Relevant External Links for IRS4 Gene

GeneLoc Exon Structure for
IRS4

Expression for IRS4 Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and SAGE for IRS4 Gene

Protein differential expression in normal tissues from HIPED for IRS4 Gene

This gene is overexpressed in Pancreatic juice (51.6) and Heart (17.4).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB, MaxQB, and MOPED for IRS4 Gene



Protein tissue co-expression partners for IRS4 Gene

Transcriptomic regulation report from SPP (The Signaling Pathways Project) for IRS4

SOURCE GeneReport for Unigene cluster for IRS4 Gene:

Hs.460872

mRNA Expression by UniProt/SwissProt for IRS4 Gene:

O14654-IRS4_HUMAN
Tissue specificity: Expressed in myoblasts. Expressed in liver and hepatocellular carcinoma.

Evidence on tissue expression from TISSUES for IRS4 Gene

  • Kidney(4.5)
  • Nervous system(2.4)
  • Pancreas(2.3)
  • Muscle(2.2)
  • Intestine(2)
  • Thyroid gland(2)
genes like me logo Genes that share expression patterns with IRS4: view

Primer products for research

No data available for mRNA expression in embryonic tissues and stem cells from LifeMap Discovery , mRNA differential expression in normal tissues and Phenotype-based relationships between genes and organs from Gene ORGANizer for IRS4 Gene

Orthologs for IRS4 Gene

This gene was present in the common ancestor of animals.

Orthologs for IRS4 Gene

Organism Taxonomy Gene Similarity Type Details
Chimpanzee
(Pan troglodytes)
Mammalia IRS4 29
  • 99.01 (n)
Cow
(Bos Taurus)
Mammalia IRS4 30
  • 81 (a)
OneToOne
Dog
(Canis familiaris)
Mammalia IRS4 30
  • 79 (a)
OneToOne
Mouse
(Mus musculus)
Mammalia Irs4 30
  • 72 (a)
OneToOne
Oppossum
(Monodelphis domestica)
Mammalia IRS4 30
  • 30 (a)
OneToOne
Chicken
(Gallus gallus)
Aves IRS4 30
  • 28 (a)
OneToOne
Lizard
(Anolis carolinensis)
Reptilia IRS4 30
  • 32 (a)
OneToOne
Zebrafish
(Danio rerio)
Actinopterygii IRS4 (1 of 2) 30
  • 27 (a)
OneToMany
irs4a 30
  • 25 (a)
OneToMany
Fruit Fly
(Drosophila melanogaster)
Insecta chico 30 31
  • 18 (a)
OneToMany
Sea Squirt
(Ciona savignyi)
Ascidiacea -- 30
  • 33 (a)
OneToMany
Species where no ortholog for IRS4 was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Eremothecium gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • African clawed frog (Xenopus laevis)
  • African malaria mosquito (Anopheles gambiae)
  • Alicante grape (Vitis vinifera)
  • Alpha proteobacteria (Wolbachia pipientis)
  • Amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • Baker's yeast (Saccharomyces cerevisiae)
  • Barley (Hordeum vulgare)
  • Beta proteobacteria (Neisseria meningitidis)
  • Bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • Common water flea (Daphnia pulex)
  • Corn (Zea mays)
  • E. coli (Escherichia coli)
  • Filamentous fungi (Aspergillus nidulans)
  • Firmicute Bacteria (Streptococcus pneumoniae)
  • Fission Yeast (Schizosaccharomyces pombe)
  • Green Algae (Chlamydomonas reinhardtii)
  • Honey Bee (Apis mellifera)
  • K. Lactis Yeast (Kluyveromyces lactis)
  • Loblloly Pine (Pinus taeda)
  • Malaria Parasite (Plasmodium falciparum)
  • Medicago Trunc (Medicago Truncatula)
  • Moss (Physcomitrella patens)
  • Orangutan (Pongo pygmaeus)
  • Pig (Sus scrofa)
  • Platypus (Ornithorhynchus anatinus)
  • Rainbow Trout (Oncorhynchus mykiss)
  • Rat (Rattus norvegicus)
  • Rice (Oryza sativa)
  • Rice Blast Fungus (Magnaporthe grisea)
  • Schistosome Parasite (Schistosoma mansoni)
  • Sea Anemone (Nematostella vectensis)
  • Sea Vase (Ciona intestinalis)
  • Sea Urchin (Strongylocentrotus purpuratus)
  • Sorghum (Sorghum bicolor)
  • Soybean (Glycine max)
  • Stem Rust Fungus (Puccinia graminis)
  • Sugarcane (Saccharum officinarum)
  • Thale Cress (Arabidopsis thaliana)
  • Tomato (Lycopersicon esculentum)
  • Toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • Tropical Clawed Frog (Silurana tropicalis)
  • Wheat (Triticum aestivum)
  • Worm (Caenorhabditis elegans)

Evolution for IRS4 Gene

ENSEMBL:
Gene Tree for IRS4 (if available)
TreeFam:
Gene Tree for IRS4 (if available)
Aminode:
Evolutionary constrained regions (ECRs) for IRS4: view image
Alliance of Genome Resources:
Additional Orthologs for IRS4

Paralogs for IRS4 Gene

Paralogs for IRS4 Gene

genes like me logo Genes that share paralogs with IRS4: view

Variants for IRS4 Gene

Sequence variations, with clinical significance, from ClinVar and Humsavar, with links to dbSNP for IRS4 Gene

SNP ID Clinical significance and condition Chr 0X pos Variation AA Info Type
1029727 Uncertain Significance: Hypothyroidism, congenital, nongoitrous, 9 108,733,130(-) G/A
NM_001379150.1(IRS4):c.3215C>T (p.Ala1072Val)
MISSENSE
rs138838170 Benign: not provided 108,736,171(-) C/T
NM_003604.2(IRS4):c.174G>A (p.Thr58=)
SYNONYMOUS
rs139268861 Benign: not provided 108,735,147(-) C/T
NM_003604.2(IRS4):c.1198G>A (p.Val400Ile)
MISSENSE
rs143866591 Benign: not provided 108,733,240(-) G/A
NM_003604.2(IRS4):c.3105C>T (p.Ala1035=)
SYNONYMOUS
rs1603336347 Pathogenic: Hypothyroidism, congenital, nongoitrous, 9 108,733,179(-) TACAGC/T
NM_003604.2(IRS4):c.3161_3165del (p.Cys1054fs)
FRAMESHIFT

dbSNP identifiers (rs#s) for variants without ClinVar clinical significance for IRS4 Gene

All consequence types are included: molecular consequences (e.g. missense, synonymous), and location-based (e.g. intron, upstream).

Structural Variations from Database of Genomic Variants (DGV) for IRS4 Gene

Variant ID Type Subtype PubMed ID
nsv519041 CNV gain 19592680

Variation tolerance for IRS4 Gene

Residual Variation Intolerance Score: 34.6% of all genes are more intolerant (likely to be disease-causing)
Gene Damage Index Score: 5.18; 69.64% of all genes are more intolerant (likely to be disease-causing)

Additional Variant Information for IRS4 Gene

Human Gene Mutation Database (HGMD)
IRS4
SNPedia medical, phenotypic, and genealogical associations of SNPs for
IRS4
Leiden Open Variation Database (LOVD)
IRS4

SNP Genotyping and Copy Number Assays for research

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot for IRS4 Gene

Disorders for IRS4 Gene

MalaCards: The human disease database

(9) MalaCards diseases for IRS4 Gene - From: OMI, CVR, GTR, COP, and GCD

Disorder Aliases PubMed IDs
hypothyroidism, congenital, nongoitrous, 9
  • chng9
hypothyroidism
  • thyroid deficiency
exostosis
  • bone spur
breast rhabdomyosarcoma
  • rhabdomyosarcoma of the breast
boutonneuse fever
  • african tick typhus
- elite association - COSMIC cancer census association via MalaCards
Search IRS4 in MalaCards View complete list of genes associated with diseases

UniProtKB/Swiss-Prot

IRS4_HUMAN
  • Hypothyroidism, congenital, non-goitrous, 9 (CHNG9) [MIM:301035]: A 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. {ECO:0000269 PubMed:30061370}. Note=The disease is caused by variants affecting the gene represented in this entry.

Additional Disease Information for IRS4

Human Genome Epidemiology Navigator
(HuGE)
Atlas
ATLAS of Genetics and Cytogenetics in Oncology and Haematology
Open Targets Platform
Open Targets Platform
genes like me logo Genes that share disorders with IRS4: view

No data available for Genatlas for IRS4 Gene

Publications for IRS4 Gene

  1. Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells. (PMID: 9553137) Fantin VR … Lavan BE (The Journal of biological chemistry 1998) 2 3 4 22
  2. A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family. (PMID: 9261155) Lavan BE … Lienhard GE (The Journal of biological chemistry 1997) 2 3 4 22
  3. Mutations in IRS4 are associated with central hypothyroidism. (PMID: 30061370) Heinen CA … Fliers E (Journal of medical genetics 2018) 3 4 72
  4. Role of insulin receptor substrate-4 in IGF-I-stimulated HEPG2 proliferation. (PMID: 17408801) Cuevas EP … Guijarro LG (Journal of hepatology 2007) 3 4 22
  5. Interaction between Brk kinase and insulin receptor substrate-4. (PMID: 15870689) Qiu H … Miller WT (Oncogene 2005) 3 4 22

Products for IRS4 Gene

Sources for IRS4 Gene