Human Gene IRS1 (ENST00000305123.6_7) from GENCODE V47lift37
  Description: insulin receptor substrate 1 (from RefSeq NM_005544.3)
Gencode Transcript: ENST00000305123.6_7
Gencode Gene: ENSG00000169047.6_9
Transcript (Including UTRs)
   Position: hg19 chr2:227,596,028-227,664,536 Size: 68,509 Total Exon Count: 2 Strand: -
Coding Region
   Position: hg19 chr2:227,659,726-227,663,454 Size: 3,729 Coding Exon Count: 1 

Page IndexSequence and LinksUniProtKB CommentsPrimersMalaCardsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated at UCSC: 2024-08-22 23:36:26

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr2:227,596,028-227,664,536)mRNA (may differ from genome)Protein (1242 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
AlphaFoldBioGPSEnsemblEntrez GeneExonPrimerGeneCards
HGNCMalacardsMGIOMIMPubMedReactome
UniProtKBWikipediaBioGrid CRISPR DB

-  Comments and Description Text from UniProtKB
  ID: IRS1_HUMAN
DESCRIPTION: RecName: Full=Insulin receptor substrate 1; Short=IRS-1;
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).
SUBUNIT: 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.
PTM: 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).
PTM: 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.
DISEASE: Polymorphisms in IRS1 may be involved in the etiology of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853].
SIMILARITY: Contains 1 IRS-type PTB domain.
SIMILARITY: Contains 1 PH domain.

-  Primer design for this transcript
 

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Click here to load the transcript sequence and exon structure into Primer3Plus

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To design primers for a non-coding sequence, zoom to a region of interest and select from the drop-down menu: View > In External Tools > Primer3


-  MalaCards Disease Associations
  MalaCards Gene Search: IRS1
Diseases sorted by gene-association score: diabetes mellitus, noninsulin-dependent* (910), mixed cell adenoma (15), gestational diabetes (10), leprechaunism (10), polycystic ovary syndrome (9), fatty liver disease (8), glucose intolerance (6), hyperglycemia (5), insulin-like growth factor i (5), glucose metabolism disease (4), acquired metabolic disease (4), endocrine pancreas disease (4), cribriform carcinoma (3), nodular nonsuppurative panniculitis (3), obesity (3), breast cancer (3), medulloblastoma (2), maturity-onset diabetes of the young (2), diabetes mellitus, insulin-dependent (2), overnutrition (2), colorectal cancer (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 15.87 RPKM in Cells - Cultured fibroblasts
Total median expression: 231.03 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -561.401082-0.519 Picture PostScript Text
3' UTR -1351.904960-0.273 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR002404 - Insln_rcpt_S1
IPR011993 - PH_like_dom
IPR001849 - Pleckstrin_homology

Pfam Domains:
PF00169 - PH domain
PF02174 - PTB domain (IRS-1 type)

SCOP Domains:
50729 - PH domain-like

Protein Data Bank (PDB) 3-D Structure
MuPIT help
1IRS - NMR MuPIT 1K3A - X-ray MuPIT 1QQG - X-ray MuPIT 2Z8C - X-ray MuPIT


ModBase Predicted Comparative 3D Structure on P35568
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-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologNo orthologNo orthologNo orthologNo orthologNo ortholog
Gene DetailsGene Details Gene Details  
Gene SorterGene Sorter Gene Sorter  
 RGDEnsembl   
      
      

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0001784 phosphotyrosine binding
GO:0004871 signal transducer activity
GO:0005068 transmembrane receptor protein tyrosine kinase adaptor activity
GO:0005080 protein kinase C binding
GO:0005088 Ras guanyl-nucleotide exchange factor activity
GO:0005158 insulin receptor binding
GO:0005159 insulin-like growth factor receptor binding
GO:0005515 protein binding
GO:0016303 1-phosphatidylinositol-3-kinase activity
GO:0042169 SH2 domain binding
GO:0043548 phosphatidylinositol 3-kinase binding
GO:0046934 phosphatidylinositol-4,5-bisphosphate 3-kinase activity

Biological Process:
GO:0000165 MAPK cascade
GO:0007165 signal transduction
GO:0008284 positive regulation of cell proliferation
GO:0008286 insulin receptor signaling pathway
GO:0010907 positive regulation of glucose metabolic process
GO:0014065 phosphatidylinositol 3-kinase signaling
GO:0032000 positive regulation of fatty acid beta-oxidation
GO:0032868 response to insulin
GO:0032869 cellular response to insulin stimulus
GO:0036092 phosphatidylinositol-3-phosphate biosynthetic process
GO:0038111 interleukin-7-mediated signaling pathway
GO:0042593 glucose homeostasis
GO:0043434 response to peptide hormone
GO:0043552 positive regulation of phosphatidylinositol 3-kinase activity
GO:0045725 positive regulation of glycogen biosynthetic process
GO:0046326 positive regulation of glucose import
GO:0046627 negative regulation of insulin receptor signaling pathway
GO:0046628 positive regulation of insulin receptor signaling pathway
GO:0046676 negative regulation of insulin secretion
GO:0046854 phosphatidylinositol phosphorylation
GO:0048009 insulin-like growth factor receptor signaling pathway
GO:0048015 phosphatidylinositol-mediated signaling
GO:0051897 positive regulation of protein kinase B signaling
GO:2001275 positive regulation of glucose import in response to insulin stimulus

Cellular Component:
GO:0005634 nucleus
GO:0005737 cytoplasm
GO:0005829 cytosol
GO:0005886 plasma membrane
GO:0005899 insulin receptor complex
GO:0005901 caveola
GO:0043231 intracellular membrane-bounded organelle


-  Descriptions from all associated GenBank mRNAs
  JB406694 - Sequence 20 from Patent WO2012072685.
BC053895 - Homo sapiens insulin receptor substrate 1, mRNA (cDNA clone MGC:61462 IMAGE:6144252), complete cds.
S62539 - insulin receptor substrate-1 [human, skeletal muscle, mRNA, 5828 nt].
JD543852 - Sequence 524876 from Patent EP1572962.
JD503022 - Sequence 484046 from Patent EP1572962.
JD288404 - Sequence 269428 from Patent EP1572962.
JD378953 - Sequence 359977 from Patent EP1572962.
JD338642 - Sequence 319666 from Patent EP1572962.
JD189202 - Sequence 170226 from Patent EP1572962.
JD493885 - Sequence 474909 from Patent EP1572962.
JD235293 - Sequence 216317 from Patent EP1572962.
KJ891488 - Synthetic construct Homo sapiens clone ccsbBroadEn_00882 IRS1 gene, encodes complete protein.
EU831611 - Synthetic construct Homo sapiens clone HAIB:100066640; DKFZo007C0819 insulin receptor substrate 1 protein (IRS1) gene, encodes complete protein.
EU831698 - Synthetic construct Homo sapiens clone HAIB:100066727; DKFZo003C0820 insulin receptor substrate 1 protein (IRS1) gene, encodes complete protein.
AB384351 - Synthetic construct DNA, clone: pF1KSDB0002, Homo sapiens IRS1 gene for insulin receptor substrate 1, complete cds, without stop codon, in Flexi system.
JD477932 - Sequence 458956 from Patent EP1572962.
JD298594 - Sequence 279618 from Patent EP1572962.
JD395087 - Sequence 376111 from Patent EP1572962.
JD308079 - Sequence 289103 from Patent EP1572962.
JD136759 - Sequence 117783 from Patent EP1572962.
JD393725 - Sequence 374749 from Patent EP1572962.
JD519937 - Sequence 500961 from Patent EP1572962.
JD398134 - Sequence 379158 from Patent EP1572962.
JD460269 - Sequence 441293 from Patent EP1572962.
JD563024 - Sequence 544048 from Patent EP1572962.
JD277239 - Sequence 258263 from Patent EP1572962.
JD481001 - Sequence 462025 from Patent EP1572962.
JD356153 - Sequence 337177 from Patent EP1572962.
JD396228 - Sequence 377252 from Patent EP1572962.
JD398264 - Sequence 379288 from Patent EP1572962.
JD519417 - Sequence 500441 from Patent EP1572962.
JD494205 - Sequence 475229 from Patent EP1572962.
JD390543 - Sequence 371567 from Patent EP1572962.
JD169905 - Sequence 150929 from Patent EP1572962.
JD196376 - Sequence 177400 from Patent EP1572962.
JD318230 - Sequence 299254 from Patent EP1572962.
JD416229 - Sequence 397253 from Patent EP1572962.
JD138751 - Sequence 119775 from Patent EP1572962.
JD325610 - Sequence 306634 from Patent EP1572962.
JD308392 - Sequence 289416 from Patent EP1572962.
JD185218 - Sequence 166242 from Patent EP1572962.
JD141750 - Sequence 122774 from Patent EP1572962.
JD227798 - Sequence 208822 from Patent EP1572962.
MB121707 - JP 2019512489-A/71: MICRORNAS AND METHODS OF THEIR USE.

-  Biochemical and Signaling Pathways
  BioCarta from NCI Cancer Genome Anatomy Project
h_eif4Pathway - Regulation of eIF4e and p70 S6 Kinase
h_ghPathway - Growth Hormone Signaling Pathway
h_il4Pathway - IL 4 signaling pathway
h_igf1rPathway - Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation
h_igf1Pathway - IGF-1 Signaling Pathway
h_il2rbPathway - IL-2 Receptor Beta Chain in T cell Activation
h_insulinPathway - Insulin Signaling Pathway

Reactome (by CSHL, EBI, and GO)

Protein P35568 (Reactome details) participates in the following event(s):

R-HSA-74707 Binding of IRS to insulin receptor
R-HSA-74747 Dephosphorylation of p-Y-IRS1,p-Y-IRS2
R-HSA-198211 Active TRKA binds IRS1/2
R-HSA-1168423 JAK2 phosphorylation of IRS-1/2
R-HSA-2671873 Phosphorylated LEP:LEPR:JAK2:SH2B1 Binds IRS1/2
R-HSA-74736 GRB2-1:SOS1 binds p-IRS1,p-IRS2
R-HSA-74737 p-Y-IRS1,p-Y-IRS2 bind PI3K
R-HSA-74712 Dissociation of IRS-P from insulin receptor
R-HSA-5686315 GRB2:p-4S-SOS1:p-Y-IRS1,p-Y-IRS2 dissociates
R-HSA-2428930 IGF1,2:p-Y1161,1165,1166-IGF1R binds IRS1,4
R-HSA-74711 Phosphorylation of IRS
R-HSA-198295 TRKA phosphorylates IRS
R-HSA-2671862 JAK2 Phosphorylates IRS in Response to Leptin
R-HSA-109823 MAPK3,(MAPK1) phosphorylates GRB2-1:SOS1:p-Y-IRS1,p-Y-IRS2
R-HSA-198315 Active IRS recruits PI3K to the plasma membrane and activates it
R-HSA-2428926 IGF1,2:p-Y1161,1165,1166-IGF1R phosphorylates IRS1,2,4
R-HSA-109817 GRB2:SOS1:p-Y-IRS1,p-Y-IRS2 mediated nucleotide exchange of RAS
R-HSA-198266 PI3K produces PIP3 and other phosphatidyl inositides
R-HSA-109699 PI3K-containing complexes phosphorylate PIP2 to PIP3
R-HSA-5672965 RAS GEFs promote RAS nucleotide exchange
R-HSA-2400009 PI3K inhibitors block PI3K catalytic activity
R-HSA-2316434 PI3K phosphorylates PIP2 to PIP3
R-HSA-74713 IRS activation
R-HSA-1266695 Interleukin-7 signaling
R-HSA-74749 Signal attenuation
R-HSA-198203 PI3K/AKT activation
R-HSA-982772 Growth hormone receptor signaling
R-HSA-2586552 Signaling by Leptin
R-HSA-112412 SOS-mediated signalling
R-HSA-109704 PI3K Cascade
R-HSA-2428928 IRS-related events triggered by IGF1R
R-HSA-74751 Insulin receptor signalling cascade
R-HSA-449147 Signaling by Interleukins
R-HSA-187037 Signaling by NTRK1 (TRKA)
R-HSA-1280215 Cytokine Signaling in Immune system
R-HSA-162582 Signal Transduction
R-HSA-112399 IRS-mediated signalling
R-HSA-2428924 IGF1R signaling cascade
R-HSA-74752 Signaling by Insulin receptor
R-HSA-166520 Signaling by NTRKs
R-HSA-168256 Immune System
R-HSA-2404192 Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
R-HSA-9006934 Signaling by Receptor Tyrosine Kinases
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-2219530 Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-1257604 PIP3 activates AKT signaling
R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-5684996 MAPK1/MAPK3 signaling
R-HSA-2219528 PI3K/AKT Signaling in Cancer
R-HSA-9006925 Intracellular signaling by second messengers
R-HSA-199418 Negative regulation of the PI3K/AKT network
R-HSA-5683057 MAPK family signaling cascades
R-HSA-5663202 Diseases of signal transduction
R-HSA-1643685 Disease

-  Other Names for This Gene
  Alternate Gene Symbols: ENST00000305123.1, ENST00000305123.2, ENST00000305123.3, ENST00000305123.4, ENST00000305123.5, IRS1_HUMAN, NM_005544, P35568, uc317nor.1, uc317nor.2
UCSC ID: ENST00000305123.6_7
RefSeq Accession: NM_005544.3
Protein: P35568 (aka IRS1_HUMAN)

-  Gene Model Information
  Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.