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IGF2R (insulin-like growth factor 2 receptor)

Written2004-03J Keith Killian
National Institutes of Health, National Cancer Institute, Laboratory of Pathology, Bldg. 10 Room 2N212, Bethesda, MD 20892, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesinsulin-like growth factor 2 receptor
Alias_symbol (synonym)CD222
MPRI
MPR1
CIMPR
M6P-R
CI-M6PR
CI-MPR
MPR300
Other aliasM6P/IGF2R
HGNC (Hugo) IGF2R
LocusID (NCBI) 3482
Atlas_Id 380
Location 6q25.3  [Link to chromosome band 6q25]
Location_base_pair Starts at 159969099 and ends at 160111502 bp from pter ( according to hg19-Feb_2009)  [Mapping IGF2R.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
IGF2R (6q25.3) / ACVR2A (2q22.3)IGF2R (6q25.3) / AKAP2 (9q31.3)IGF2R (6q25.3) / ARFGEF2 (20q13.13)
IGF2R (6q25.3) / PREP (6q21)IGF2R (6q25.3) / SYTL3 (6q25.3)IGF2R (6q25.3) / WTAP (6q25.3)
SLC25A44 (1q22) / IGF2R (6q25.3)

DNA/RNA

Note no known splice variants
Description 138376 bp
Transcription 9090 bp mRNA
Pseudogene None known

Protein

Description 2491 aa
Expression Subject to parental genomic imprinting in some viviparous mammals. Preferential transcription of maternally-derived allele in some mammals with the exception of primates and close relatives. Humans harbor a parentally imprinted differentially methylated CpG island, but human IGF2R transcripts are not preferentially maternally derived.
Function M6P/IGF2R translates to a protein whose diverse functions include lysosomal enzyme trafficking, fetal organogenesis, tumor suppression, and cytotoxic T-cell induced apoptosis. The M6P- and IGF2-binding sites are distinct within the protein, and are thought to have evolved independently, partly explaining the gamut of functions attributable to a single protein: the ancestral M6PR dates back at least 450 million years, and appears to have been a suitable platform for acquiring an IGF2 binding function in ancestral mammals roughly 150 to 200 million years ago; as with M6P-tagged molecules, bound IGF2 is targeted to lysosomes, where IGF2 is degraded. To the extent that the tumor suppressor role of M6P/IGF2R relies on IGF2 binding, the M6P/IGF2R is a very young tumor suppressor.
Homology CD-MPR

Mutations

Note Include genetic and epigenetic derangements.
Epigenetics Beyond biochemical and DNA sequence properties, M6P/IGF2R epigenetic traits have been described. In humans, there is a differentially methylated region (DMR) in intron 2 of the gene which is preferentially methylated on the maternally inherited copy of the gene; in addition, the human M6P/IGF2R resides in an asynchronously replicating genomic region, such that the gene allele inherited from the mother replicates first.

Despite these parentally pre-programmed epigenetic behaviors, human M6P/IGF2R transcription appears to be equivalent between both parentally-inherited alleles. Thus, human M6P/IGF2R alleles are encoded with information about parental origin, but this information is evidently uncoupled from transcriptional ramifications. This uncoupling is particularly intriguing in light of mouse genetic manipulations which causally link an imprinted M6p/igf2r DMR to imprinted transcription. Thus, the human M6P/IGF2R provides a rare example of uncoupling of stable gene imprinting --evidenced by somatically heritable parent-specific DNA methylation-- from stable imprinted transcription. Interestingly, the marsupial M6P/IGF2R homologue manifests parentally imprinted maternal transcription in the absence of imprinted differential methylation.

M6P/IGF2R, thus, is remarkably divergent across animal species with respect to both biochemical and epigenetic properties. Within the imprinted family of genes, M6P/IGF2R manifests a distinctive uncoupling of imprinted methylation from imprinted transcription, which frustrates efforts to establish the precise role of DNA methylation in the imprinting process. M6P/IGF2R is somewhat of a devil's advocate and a reminder that genes don't always read the journals.

Germinal Epigenetic alterations associated with fetal developmental abnormalities.
Somatic PCR-platform IGF2R LOH, microsatellite instability, and point mutations described in tumors.
Somatic mutations of M6P/IGF2R DNA sequence have been identified in human colon, liver, lung, breast and ovarian cancers, suggestive of Knudson-type two-hit oncogenetics at first glance; however, M6P/IGF2R loss of heterozygosity (LOH) is reported to precede point mutation of the remaining allele in the hepatocellular carcinoma model, in distinction from RB and other genes following the two-hit principle of Knudson. Statistically significant differences in M6P/IGF2R allelic variants have been identified between Japanese and American populations, but any functional significance has not been ascribed.

Implicated in

Note
  
Entity Development, immunity, tumorigenesis.
  

Bibliography

Mannose 6-phosphate receptors: new twists in the tale.
Ghosh P, Dahms NM, Kornfeld S
Nature reviews. Molecular cell biology. 2003 ; 4 (3) : 202-212.
PMID 12612639
 
Mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) variants in American and Japanese populations.
Killian JK, Oka Y, Jang HS, Fu X, Waterland RA, Sohda T, Sakaguchi S, Jirtle RL
Human mutation. 2001 ; 18 (1) : 25-31.
PMID 11438990
 
Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors.
Kornfeld S
Annual review of biochemistry. 1992 ; 61 : 307-330.
PMID 1323236
 
Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis.
Motyka B, Korbutt G, Pinkoski MJ, Heibein JA, Caputo A, Hobman M, Barry M, Shostak I, Sawchuk T, Holmes CF, Gauldie J, Bleackley RC
Cell. 2000 ; 103 (3) : 491-500.
PMID 11081635
 
Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions.
Sandovici I, Leppert M, Hawk PR, Suarez A, Linares Y, Sapienza C
Human molecular genetics. 2003 ; 12 (13) : 1569-1578.
PMID 12812984
 
Conservation of a maternal-specific methylation signal at the human IGF2R locus.
Smrzka OW, Faé I, Stöger R, Kurzbauer R, Fischer GF, Henn T, Weith A, Barlow DP
Human molecular genetics. 1995 ; 4 (10) : 1945-1952.
PMID 8595419
 
Imprinted expression of the Igf2r gene depends on an intronic CpG island.
Wutz A, Smrzka OW, Schweifer N, Schellander K, Wagner EF, Barlow DP
Nature. 1997 ; 389 (6652) : 745-749.
PMID 9338788
 
Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis.
Yamada T, De Souza AT, Finkelstein S, Jirtle RL
Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (19) : 10351-10355.
PMID 9294214
 
Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture.
Young LE, Fernandes K, McEvoy TG, Butterwith SC, Gutierrez CG, Carolan C, Broadbent PJ, Robinson JJ, Wilmut I, Sinclair KD
Nature genetics. 2001 ; 27 (2) : 153-154.
PMID 11175780
 

Citation

This paper should be referenced as such :
Killian, JK
IGF2R (insulin-like growth factor 2 receptor)
Atlas Genet Cytogenet Oncol Haematol. 2004;8(2):65-66.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/IGF2RID380.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Liver: Hepatocellular carcinoma


External links

Nomenclature
HGNC (Hugo)IGF2R   5467
LRG (Locus Reference Genomic)LRG_1036
Cards
AtlasIGF2RID380
Entrez_Gene (NCBI)IGF2R  3482  insulin like growth factor 2 receptor
AliasesCD222; CI-M6PR; CIMPR; M6P-R; 
M6P/IGF2R; MPR; MPR1; MPR300; MPRI
GeneCards (Weizmann)IGF2R
Ensembl hg19 (Hinxton)ENSG00000197081 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000197081 [Gene_View]  chr6:159969099-160111502 [Contig_View]  IGF2R [Vega]
ICGC DataPortalENSG00000197081
TCGA cBioPortalIGF2R
AceView (NCBI)IGF2R
Genatlas (Paris)IGF2R
WikiGenes3482
SOURCE (Princeton)IGF2R
Genetics Home Reference (NIH)IGF2R
Genomic and cartography
GoldenPath hg38 (UCSC)IGF2R  -     chr6:159969099-160111502 +  6q25.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)IGF2R  -     6q25.3   [Description]    (hg19-Feb_2009)
EnsemblIGF2R - 6q25.3 [CytoView hg19]  IGF2R - 6q25.3 [CytoView hg38]
Mapping of homologs : NCBIIGF2R [Mapview hg19]  IGF2R [Mapview hg38]
OMIM114550   147280   
Gene and transcription
Genbank (Entrez)AB209668 AK300848 BC010121 BC172256 J03528
RefSeq transcript (Entrez)NM_000876
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)IGF2R
Cluster EST : UnigeneHs.673278 [ NCBI ]
CGAP (NCI)Hs.673278
Alternative Splicing GalleryENSG00000197081
Gene ExpressionIGF2R [ NCBI-GEO ]   IGF2R [ EBI - ARRAY_EXPRESS ]   IGF2R [ SEEK ]   IGF2R [ MEM ]
Gene Expression Viewer (FireBrowse)IGF2R [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3482
GTEX Portal (Tissue expression)IGF2R
Human Protein AtlasENSG00000197081-IGF2R [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP11717   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP11717  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP11717
Splice isoforms : SwissVarP11717
PhosPhoSitePlusP11717
Domaine pattern : Prosite (Expaxy)FN2_1 (PS00023)    FN2_2 (PS51092)   
Domains : Interpro (EBI)CIMR    FN_type2_col-bd    Kringle-like    Man6P_isomerase_rcpt-bd_dom   
Domain families : Pfam (Sanger)CIMR (PF00878)    fn2 (PF00040)   
Domain families : Pfam (NCBI)pfam00878    pfam00040   
Domain families : Smart (EMBL)CIMR (SM01404)  FN2 (SM00059)  
Conserved Domain (NCBI)IGF2R
DMDM Disease mutations3482
Blocks (Seattle)IGF2R
PDB (SRS)1E6F    1GP0    1GP3    1GQB    1JPL    1JWG    1LF8    2CNJ    2L29    2L2A    2M68    2M6T    2V5N    2V5O    2V5P    5IEI   
PDB (PDBSum)1E6F    1GP0    1GP3    1GQB    1JPL    1JWG    1LF8    2CNJ    2L29    2L2A    2M68    2M6T    2V5N    2V5O    2V5P    5IEI   
PDB (IMB)1E6F    1GP0    1GP3    1GQB    1JPL    1JWG    1LF8    2CNJ    2L29    2L2A    2M68    2M6T    2V5N    2V5O    2V5P    5IEI   
PDB (RSDB)1E6F    1GP0    1GP3    1GQB    1JPL    1JWG    1LF8    2CNJ    2L29    2L2A    2M68    2M6T    2V5N    2V5O    2V5P    5IEI   
Structural Biology KnowledgeBase1E6F    1GP0    1GP3    1GQB    1JPL    1JWG    1LF8    2CNJ    2L29    2L2A    2M68    2M6T    2V5N    2V5O    2V5P    5IEI   
SCOP (Structural Classification of Proteins)1E6F    1GP0    1GP3    1GQB    1JPL    1JWG    1LF8    2CNJ    2L29    2L2A    2M68    2M6T    2V5N    2V5O    2V5P    5IEI   
CATH (Classification of proteins structures)1E6F    1GP0    1GP3    1GQB    1JPL    1JWG    1LF8    2CNJ    2L29    2L2A    2M68    2M6T    2V5N    2V5O    2V5P    5IEI   
SuperfamilyP11717
Human Protein Atlas [tissue]ENSG00000197081-IGF2R [tissue]
Peptide AtlasP11717
HPRD00928
IPIIPI00289819   IPI00930044   IPI00930184   
Protein Interaction databases
DIP (DOE-UCLA)P11717
IntAct (EBI)P11717
FunCoupENSG00000197081
BioGRIDIGF2R
STRING (EMBL)IGF2R
ZODIACIGF2R
Ontologies - Pathways
QuickGOP11717
Ontology : AmiGOliver development  glycoprotein binding  G-protein alpha-subunit binding  retinoic acid binding  receptor activity  G-protein coupled receptor activity  insulin-like growth factor-activated receptor activity  transporter activity  protein binding  mannose binding  extracellular space  nuclear envelope lumen  lysosome  lysosomal membrane  endosome  early endosome  late endosome  Golgi apparatus  trans-Golgi network  plasma membrane  integral component of plasma membrane  focal adhesion  receptor-mediated endocytosis  signal transduction  G-protein coupled receptor signaling pathway  spermatogenesis  post-embryonic development  cell surface  membrane  enzyme binding  clathrin coat  transport vesicle  endocytic vesicle  trans-Golgi network transport vesicle  clathrin-coated vesicle membrane  secretory granule membrane  animal organ regeneration  insulin-like growth factor II binding  response to retinoic acid  trans-Golgi network membrane  identical protein binding  positive regulation of apoptotic process  neutrophil degranulation  insulin-like growth factor receptor signaling pathway  perinuclear region of cytoplasm  phosphoprotein binding  membrane organization  extracellular exosome  
Ontology : EGO-EBIliver development  glycoprotein binding  G-protein alpha-subunit binding  retinoic acid binding  receptor activity  G-protein coupled receptor activity  insulin-like growth factor-activated receptor activity  transporter activity  protein binding  mannose binding  extracellular space  nuclear envelope lumen  lysosome  lysosomal membrane  endosome  early endosome  late endosome  Golgi apparatus  trans-Golgi network  plasma membrane  integral component of plasma membrane  focal adhesion  receptor-mediated endocytosis  signal transduction  G-protein coupled receptor signaling pathway  spermatogenesis  post-embryonic development  cell surface  membrane  enzyme binding  clathrin coat  transport vesicle  endocytic vesicle  trans-Golgi network transport vesicle  clathrin-coated vesicle membrane  secretory granule membrane  animal organ regeneration  insulin-like growth factor II binding  response to retinoic acid  trans-Golgi network membrane  identical protein binding  positive regulation of apoptotic process  neutrophil degranulation  insulin-like growth factor receptor signaling pathway  perinuclear region of cytoplasm  phosphoprotein binding  membrane organization  extracellular exosome  
Pathways : KEGGLysosome   
REACTOMEP11717 [protein]
REACTOME PathwaysR-HSA-8856828 [pathway]   
NDEx NetworkIGF2R
Atlas of Cancer Signalling NetworkIGF2R
Wikipedia pathwaysIGF2R
Orthology - Evolution
OrthoDB3482
GeneTree (enSembl)ENSG00000197081
Phylogenetic Trees/Animal Genes : TreeFamIGF2R
HOVERGENP11717
HOGENOMP11717
Homologs : HomoloGeneIGF2R
Homology/Alignments : Family Browser (UCSC)IGF2R
Gene fusions - Rearrangements
Fusion : MitelmanIGF2R/ACVR2A [6q25.3/2q22.3]  
Fusion : MitelmanIGF2R/ARFGEF2 [6q25.3/20q13.13]  [t(6;20)(q25;q13)]  
Fusion : MitelmanIGF2R/PREP [6q25.3/6q21]  [t(6;6)(q21;q25)]  
Fusion : MitelmanIGF2R/SYTL3 [6q25.3/6q25.3]  [t(6;6)(q25;q25)]  
Fusion : MitelmanIGF2R/WTAP [6q25.3/6q25.3]  [t(6;6)(q25;q25)]  
Fusion: TCGAIGF2R 6q25.3 ACVR2A 2q22.3 BRCA
Fusion: TCGAIGF2R 6q25.3 ARFGEF2 20q13.13 THCA
Fusion: TCGAIGF2R 6q25.3 PREP 6q21 BRCA
Fusion: TCGAIGF2R 6q25.3 SYTL3 6q25.3 LUSC
Fusion: TCGAIGF2R 6q25.3 WTAP 6q25.3 LUAD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIGF2R [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)IGF2R
dbVarIGF2R
ClinVarIGF2R
1000_GenomesIGF2R 
Exome Variant ServerIGF2R
ExAC (Exome Aggregation Consortium)ENSG00000197081
GNOMAD BrowserENSG00000197081
Genetic variants : HAPMAP3482
Genomic Variants (DGV)IGF2R [DGVbeta]
DECIPHERIGF2R [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisIGF2R 
Mutations
ICGC Data PortalIGF2R 
TCGA Data PortalIGF2R 
Broad Tumor PortalIGF2R
OASIS PortalIGF2R [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICIGF2R  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDIGF2R
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
BioMutasearch IGF2R
DgiDB (Drug Gene Interaction Database)IGF2R
DoCM (Curated mutations)IGF2R (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)IGF2R (select a term)
intoGenIGF2R
NCG5 (London)IGF2R
Cancer3DIGF2R(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM114550    147280   
Orphanet
MedgenIGF2R
Genetic Testing Registry IGF2R
NextProtP11717 [Medical]
TSGene3482
GENETestsIGF2R
Target ValidationIGF2R
Huge Navigator IGF2R [HugePedia]
snp3D : Map Gene to Disease3482
BioCentury BCIQIGF2R
ClinGenIGF2R (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3482
Chemical/Pharm GKB GenePA29701
Clinical trialIGF2R
Miscellaneous
canSAR (ICR)IGF2R (select the gene name)
Probes
Litterature
PubMed203 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineIGF2R
EVEXIGF2R
GoPubMedIGF2R
iHOPIGF2R
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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