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IGF1R (insulin-like growth factor 1 receptor)

Written2008-09Itay Bentov, Haim Werner
Department of Human Molecular Genetics, Biochemistry, Sackler School of Medecine, Tel Aviv University,Tel Aviv 69978, ISRAEL

(Note : for Links provided by Atlas : click)

Identity

Alias_namesinsulin-like growth factor 1 receptor
Alias_symbol (synonym)JTK13
CD221
IGFIR
MGC18216
IGFR
Other aliasMGC142170
MGC142172
HGNC (Hugo) IGF1R
LocusID (NCBI) 3480
Atlas_Id 40928
Location 15q26.3  [Link to chromosome band 15q26]
Location_base_pair Starts at 98648539 and ends at 98964530 bp from pter ( according to hg19-Feb_2009)  [Mapping IGF1R.png]
Fusion genes
(updated 2016)
AKAP13 (15q25.3) / IGF1R (15q26.3)FAM13A (4q22.1) / IGF1R (15q26.3)IGF1R (15q26.3) / BBX (3q13.12)
IGF1R (15q26.3) / IGF1R (15q26.3)IGF1R (15q26.3) / MALAT1 (11q13.1)IGF1R (15q26.3) / MAPK6 (15q21.2)
IGF1R (15q26.3) / RHOT2 (16p13.3)IGF1R (15q26.3) / TTC23 (15q26.3)

DNA/RNA

Description The IGF1R gene contains 21 exons spanning approximately 100-kb of genomic DNA.
Transcription The IGF1R mRNA is a 11242-base, single-stranded linear molecule. Various hormones and growth factors were shown to regulate IGF1R gene transcription. Specifically, growth factors and oncogenic agents associated with positive stimulation of cell division were shown to upregulate IGF1R gene expression whereas negative modulators of cell growth (e.g., tumor suppressors) usually cause a reduction in IGF1R gene expression. Growth factors that stimulate IGF1R gene transcription include, among others, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). In addition, IGF1R gene expression is regulated by steroid hormones. Thus, estradiol was shown to increase, while progesterone decreased, IGF1R mRNA levels in breast cancer cells.

Protein

Description The IGF1R is a cell-surface tyrosine kinase receptor that is synthesized as a single polypeptide chain which is then processed to yield an around 180-kDa glycopeptide. The length of the IGF1R precursor is 1367 amino acids. Precursor chains include a 30-amino acid leader peptide rich in hydrophobic residues, which is involved in the transfer of the nascent protein into the endoplasmic reticulum. Partially processed proreceptors form disulfide-linked dimers that are subsequently glycosylated and proteolytically cleaved at a basic tetrapeptide sequence to yield mature α and ® subunits. The mature heterotetramers have a β-α-α-β conformation.
The α subunit is entirely extracellular and includes a cysteine-rich region and several potential N-linked glycosylation sites (Asn-X-Ser/Thr motifs). The cysteine-rich domain of the IGF1R is important for high-affinity IGF1 binding. The ® subunit features a unique hydrophobic sequence that constitutes the transmembrane domain. The cytoplasmic portion of the ® subunit contains a tyrosine kinase enzymatic domain. Inside this catalytic region there is a glycine-rich conserved element that participates in the transfer of the phosphate moiety of ATP to specific substrates.
Expression The IGF1R is abundantly expressed in the embryo, with significant reduction in expression levels at adult stages.
Localisation The IGF1R is essentially expressed by most organs and tissues. Very high levels are detected in brain. Extremely low levels are seen in liver, due to downregulation by hepatic IGF1.
Function The IGF1R is involved in growth, development, and differentiation processes. The IGF1R displays a very strong antiapoptotic activity and protects IGF1R-expressing cells from programmed cell death.
IGF1R is vital for cell survival, as illustrated by the lethal phenotype of mice in which the IGF1R gene was disrupted by homologous recombination. During normal ontogenesis, the IGF1R is expressed at every developmental period, including the oocyte stage. Late embryonic and adult stages, in which the percentage of rapidly proliferating cells declines, are associated with an overall reduction in IGF1R mRNA levels.
IGF1R is involved in normal growth, development, and differentiation processes. IGF1R mediates the biological roles of both the IGF1 and IGF2 ligands. IGF1R binds IGF1 and IGF2 with high affinity, and insulin with significantly reduced affinity. IGF1R displays a very potent antiapoptotic activity, protecting IGF1R-expressing cells from programed cell death. Activation of the IGF1R by locally-produced or circulating IGF1 or IGF2 leads to autophosphorylation of the tyrosine kinase domain, with ensuing activation of the Ras-Raf-MAP kinase and PI3K-PKB/Akt signaling pathways. Activation of these cytoplasmic mediators is critical in order for the IGF1R to exert its mitogenic and antiapoptotic activities.
The biological actions of the IGF1R are modulated by a family of IGF-binding proteins (IGFBPs) that includes at least six members (IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6). IGFBPs control IGF1R action by regulating the bioavailability of the IGF1 and IGF2 ligands. The affinity of the IGFBPs for the ligands is 1-2 orders of magnitude higher than the affinity exhibited by the receptor. IGFBPs usually display inhibitory types of activities however, under certain circumstances, IGFBPs may also stimulate IGF1 action.

Mutations

Note IGF1R mutations are very rare, suggesting that homozygous mutations are a lethal condition. Recently, IGF1R mutations were described in two cohorts of children. The first cohort consisted of children with unexplained intrauterine growth restriction and subsequent short stature, and the second group included children with short stature and high circulating IGF1 levels. A compound heterozygote for point mutations in IGF1R exon 2 was identified in a girl from the first group. Fibroblasts cultured from the patient had decreased IGF1R binding and IGF1-stimulated phosphorylation. In the second cohort a boy was identified with a nonsense mutation, leading to reduced IGF1R expression.
In a family harboring a ring chromosome 15, hemizygotes for the IGF1R locus showed severe growth failure, while a patient possessing two copies of the gene had borderline stature. On the other hand, a patient with three IGF1R gene copies due to a partial duplication of the long arm of chromosome 15, presented with height and weight above the 97th percentile and showed accelerated cellular growth.

Implicated in

Note
  
Entity Various tumors
Note Clinical and experimental data collected over the past 25 years have suggested that the IGF1R gene exhibits a pattern of expression in malignant cells that reflects its pro-survival role. Using a variety of techniques, including IGF binding and radio-receptor assays, Northern and Western blottings, and immunohistochemical and in situ hybridization analyses, most studies consistently showed that the IGF1R is expressed at high levels in primary tumors and cancer-derived cells. These tumors include, among others, breast, prostate, ovarian, colon, hematopoietic, rhabdomyosarcoma, and renal cancers. These augmented IGF1R levels reflect a reversal to more primitive, less differentiated, ontogenetic stages that, in most species and body organs, are characterized by very high concentrations of IGF1R mRNA and IGF binding sites. Whereas the molecular mechanisms that lead to increased IGF1R gene expression in cancer remain largely unexplained, the dogma that emerged postulated that IGF1R expression is a fundamental prerequisite for cellular transformation. The appeal of this paradigm resides in the fact that enhanced IGF1R levels and IGF1 signaling are considered key factors, indispensable for the cell, in order to adopt proliferative/oncogenic pathways.
Anti-IGF1R strategies (e.g., humanized IGF1R antibodies, low molecular weight tyrosine kinase inhibitors, etc.) are currently being developed in order to target the IGF1R as a clinically relevant therapeutic target.
  

Bibliography

IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation.
Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD; Intrauterine Growth Retardation (IUGR) Study Group.
N Engl J Med. 2003 Dec 4;349(23):2211-22.
PMID 14657428
 
Role of insulin-like growth factors in embryonic and postnatal growth.
Baker J, Liu JP, Robertson EJ, Efstratiadis A.
Cell. 1993 Oct 8;75(1):73-82.
PMID 8402902
 
IGF, IGF receptor and overgrowth syndromes.
Bentov I, Werner H.
Pediatr Endocrinol Rev. 2004 Jun;1(4):352-60. (REVIEW)
PMID 16437028
 
Type I insulin-like growth factor receptor gene expression in normal human breast tissue treated with oestrogen and progesterone.
Clarke RB, Howell A, Anderson E.
Br J Cancer. 1997;75(2):251-7.
PMID 9010034
 
Differential regulation of insulin-like growth factor-I (IGF-I) receptor gene expression by IGF-I and basic fibroblastic growth factor.
Hernandez-Sanchez C, Werner H, Roberts CT Jr, Woo EJ, Hum DW, Rosenthal SM, LeRoith D.
J Biol Chem. 1997 Feb 21;272(8):4663-70.
PMID 9030517
 
IGF signaling defects as causes of growth failure and IUGR.
Klammt J, Pfaffle R, Werner H, Kiess W.
Trends Endocrinol Metab. 2008 Aug;19(6):197-205.
PMID 18515143
 
Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene.
Okubo Y, Siddle K, Firth H, O'Rahilly S, Wilson LC, Willatt L, Fukushima T, Takahashi S, Petry CJ, Saukkonen T, Stanhope R, Dunger DB.
J Clin Endocrinol Metab. 2003 Dec;88(12):5981-8.
PMID 14671200
 
Hemizygosity at the insulin-like growth factor I receptor (IGF1R) locus and growth failure in the ring chromosome 15 syndrome.
Peoples R, Milatovich A, Francke U.
Cytogenet Cell Genet. 1995;70(3-4):228-34.
PMID 7789178
 
Platelet-derived growth factor increases the activity of the promoter of the insulin-like growth factor-1 (IGF-1) receptor gene.
Rubini M, Werner H, Gandini E, Roberts CT Jr, LeRoith D, Baserga R.
Exp Cell Res. 1994 Apr;211(2):374-9.
PMID 8143786
 
The role of the insulin-like growth factor system in human cancer.
Werner H, LeRoith D.
Adv Cancer Res. 1996;68:183-223. (REVIEW)
PMID 8712068
 
The insulin-like growth factor-I receptor gene: a downstream target for oncogene and tumor suppressor action.
Werner H, Maor S.
Trends Endocrinol Metab. 2006 Aug;17(6):236-42.
PMID 16815029
 

Citation

This paper should be referenced as such :
Bentov, Y ; Werner, H
IGF1R (insulin-like growth factor 1 receptor)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(8):559-561.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/IGF1RID40928ch15q26.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Colon: Colorectal adenocarcinoma
Breast: Ductal carcinoma


External links

Nomenclature
HGNC (Hugo)IGF1R   5465
LRG (Locus Reference Genomic)LRG_1055
Cards
AtlasIGF1RID40928ch15q26
Entrez_Gene (NCBI)IGF1R  3480  insulin like growth factor 1 receptor
AliasesCD221; IGFIR; IGFR; JTK13
GeneCards (Weizmann)IGF1R
Ensembl hg19 (Hinxton)ENSG00000140443 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000140443 [Gene_View]  chr15:98648539-98964530 [Contig_View]  IGF1R [Vega]
ICGC DataPortalENSG00000140443
TCGA cBioPortalIGF1R
AceView (NCBI)IGF1R
Genatlas (Paris)IGF1R
WikiGenes3480
SOURCE (Princeton)IGF1R
Genetics Home Reference (NIH)IGF1R
Genomic and cartography
GoldenPath hg38 (UCSC)IGF1R  -     chr15:98648539-98964530 +  15q26.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)IGF1R  -     15q26.3   [Description]    (hg19-Feb_2009)
EnsemblIGF1R - 15q26.3 [CytoView hg19]  IGF1R - 15q26.3 [CytoView hg38]
Mapping of homologs : NCBIIGF1R [Mapview hg19]  IGF1R [Mapview hg38]
OMIM147370   270450   
Gene and transcription
Genbank (Entrez)AB425196 AF020763 AK310188 AY429545 BC010607
RefSeq transcript (Entrez)NM_000875 NM_001291858 NM_152452
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)IGF1R
Cluster EST : UnigeneHs.714012 [ NCBI ]
CGAP (NCI)Hs.714012
Alternative Splicing GalleryENSG00000140443
Gene ExpressionIGF1R [ NCBI-GEO ]   IGF1R [ EBI - ARRAY_EXPRESS ]   IGF1R [ SEEK ]   IGF1R [ MEM ]
Gene Expression Viewer (FireBrowse)IGF1R [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3480
GTEX Portal (Tissue expression)IGF1R
Protein : pattern, domain, 3D structure
UniProt/SwissProtP08069   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP08069  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP08069
Splice isoforms : SwissVarP08069
Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.12.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
PhosPhoSitePlusP08069
Domaine pattern : Prosite (Expaxy)FN3 (PS50853)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)    RECEPTOR_TYR_KIN_II (PS00239)   
Domains : Interpro (EBI)###############################################################################################################################################################################################################################################################                                                           
Domain families : Pfam (Sanger)Furin-like (PF00757)    Pkinase_Tyr (PF07714)    Recep_L_domain (PF01030)   
Domain families : Pfam (NCBI)pfam00757    pfam07714    pfam01030   
Domain families : Smart (EMBL)FN3 (SM00060)  FU (SM00261)  TyrKc (SM00219)  
Conserved Domain (NCBI)IGF1R
DMDM Disease mutations3480
Blocks (Seattle)IGF1R
PDB (SRS)1IGR    1JQH    1K3A    1M7N    1P4O    2OJ9    2ZM3    3D94    3F5P    3I81    3LVP    3LW0    3NW5    3NW6    3NW7    3O23    3QQU    4D2R    4XSS    5FXQ    5FXR    5FXS    5HZN   
PDB (PDBSum)1IGR    1JQH    1K3A    1M7N    1P4O    2OJ9    2ZM3    3D94    3F5P    3I81    3LVP    3LW0    3NW5    3NW6    3NW7    3O23    3QQU    4D2R    4XSS    5FXQ    5FXR    5FXS    5HZN   
PDB (IMB)1IGR    1JQH    1K3A    1M7N    1P4O    2OJ9    2ZM3    3D94    3F5P    3I81    3LVP    3LW0    3NW5    3NW6    3NW7    3O23    3QQU    4D2R    4XSS    5FXQ    5FXR    5FXS    5HZN   
PDB (RSDB)1IGR    1JQH    1K3A    1M7N    1P4O    2OJ9    2ZM3    3D94    3F5P    3I81    3LVP    3LW0    3NW5    3NW6    3NW7    3O23    3QQU    4D2R    4XSS    5FXQ    5FXR    5FXS    5HZN   
Structural Biology KnowledgeBase1IGR    1JQH    1K3A    1M7N    1P4O    2OJ9    2ZM3    3D94    3F5P    3I81    3LVP    3LW0    3NW5    3NW6    3NW7    3O23    3QQU    4D2R    4XSS    5FXQ    5FXR    5FXS    5HZN   
SCOP (Structural Classification of Proteins)1IGR    1JQH    1K3A    1M7N    1P4O    2OJ9    2ZM3    3D94    3F5P    3I81    3LVP    3LW0    3NW5    3NW6    3NW7    3O23    3QQU    4D2R    4XSS    5FXQ    5FXR    5FXS    5HZN   
CATH (Classification of proteins structures)1IGR    1JQH    1K3A    1M7N    1P4O    2OJ9    2ZM3    3D94    3F5P    3I81    3LVP    3LW0    3NW5    3NW6    3NW7    3O23    3QQU    4D2R    4XSS    5FXQ    5FXR    5FXS    5HZN   
SuperfamilyP08069
Human Protein AtlasENSG00000140443
Peptide AtlasP08069
HPRD00932
IPIIPI00027232   IPI00026288   IPI00655523   
Protein Interaction databases
DIP (DOE-UCLA)P08069
IntAct (EBI)P08069
FunCoupENSG00000140443
BioGRIDIGF1R
STRING (EMBL)IGF1R
ZODIACIGF1R
Ontologies - Pathways
QuickGOP08069
Ontology : AmiGOprotein tyrosine kinase activity  protein tyrosine kinase activity  protein tyrosine kinase activity  insulin-like growth factor-activated receptor activity  insulin receptor binding  protein binding  insulin-like growth factor binding  ATP binding  plasma membrane  plasma membrane  integral component of plasma membrane  immune response  signal transduction  positive regulation of cell proliferation  insulin receptor signaling pathway  phosphatidylinositol 3-kinase signaling  membrane  positive regulation of cell migration  insulin-like growth factor I binding  insulin-like growth factor I binding  alphav-beta3 integrin-IGF-1-IGF1R complex  peptidyl-tyrosine autophosphorylation  identical protein binding  negative regulation of apoptotic process  intracellular membrane-bounded organelle  receptor complex  phosphatidylinositol 3-kinase binding  insulin binding  insulin receptor substrate binding  positive regulation of DNA replication  regulation of JNK cascade  protein autophosphorylation  insulin-like growth factor receptor signaling pathway  phosphatidylinositol-mediated signaling  protein tetramerization  inactivation of MAPKK activity  
Ontology : EGO-EBIprotein tyrosine kinase activity  protein tyrosine kinase activity  protein tyrosine kinase activity  insulin-like growth factor-activated receptor activity  insulin receptor binding  protein binding  insulin-like growth factor binding  ATP binding  plasma membrane  plasma membrane  integral component of plasma membrane  immune response  signal transduction  positive regulation of cell proliferation  insulin receptor signaling pathway  phosphatidylinositol 3-kinase signaling  membrane  positive regulation of cell migration  insulin-like growth factor I binding  insulin-like growth factor I binding  alphav-beta3 integrin-IGF-1-IGF1R complex  peptidyl-tyrosine autophosphorylation  identical protein binding  negative regulation of apoptotic process  intracellular membrane-bounded organelle  receptor complex  phosphatidylinositol 3-kinase binding  insulin binding  insulin receptor substrate binding  positive regulation of DNA replication  regulation of JNK cascade  protein autophosphorylation  insulin-like growth factor receptor signaling pathway  phosphatidylinositol-mediated signaling  protein tetramerization  inactivation of MAPKK activity  
Pathways : BIOCARTA [Genes]   
Pathways : KEGG   
REACTOMEP08069 [protein]
REACTOME PathwaysR-HSA-2428933 [pathway]   
NDEx NetworkIGF1R
Atlas of Cancer Signalling NetworkIGF1R
Wikipedia pathwaysIGF1R
Orthology - Evolution
OrthoDB3480
GeneTree (enSembl)ENSG00000140443
Phylogenetic Trees/Animal Genes : TreeFamIGF1R
HOVERGENP08069
HOGENOMP08069
Homologs : HomoloGeneIGF1R
Homology/Alignments : Family Browser (UCSC)IGF1R
Gene fusions - Rearrangements
Fusion : MitelmanAKAP13/IGF1R [15q25.3/15q26.3]  [t(15;15)(q25;q26)]  
Fusion: TCGAAKAP13 15q25.3 IGF1R 15q26.3 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIGF1R [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)IGF1R
dbVarIGF1R
ClinVarIGF1R
1000_GenomesIGF1R 
Exome Variant ServerIGF1R
ExAC (Exome Aggregation Consortium)IGF1R (select the gene name)
Genetic variants : HAPMAP3480
Genomic Variants (DGV)IGF1R [DGVbeta]
DECIPHERIGF1R [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisIGF1R 
Mutations
ICGC Data PortalIGF1R 
TCGA Data PortalIGF1R 
Broad Tumor PortalIGF1R
OASIS PortalIGF1R [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICIGF1R  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDIGF1R
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
BioMutasearch IGF1R
DgiDB (Drug Gene Interaction Database)IGF1R
DoCM (Curated mutations)IGF1R (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)IGF1R (select a term)
intoGenIGF1R
NCG5 (London)IGF1R
Cancer3DIGF1R(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM147370    270450   
Orphanet11049   
MedgenIGF1R
Genetic Testing Registry IGF1R
NextProtP08069 [Medical]
TSGene3480
GENETestsIGF1R
Target ValidationIGF1R
Huge Navigator IGF1R [HugePedia]
snp3D : Map Gene to Disease3480
BioCentury BCIQIGF1R
ClinGenIGF1R (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3480
Chemical/Pharm GKB GenePA29698
Clinical trialIGF1R
Miscellaneous
canSAR (ICR)IGF1R (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineIGF1R
EVEXIGF1R
GoPubMedIGF1R
iHOPIGF1R
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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