IGF2R (insulin-like growth factor 2 receptor)

2004-03-01   J Keith Killian 

National Institutes of Health, National Cancer Institute, Laboratory of Pathology, Bldg. 10 Room 2N212, Bethesda, MD 20892, USA

Identity

HGNC
LOCATION
6q25.3
LOCUSID
ALIAS
CD222,CI-M6PR,CIMPR,M6P-R,M6P/IGF2R,MPR
FUSION GENES

DNA/RNA

Note

no known splice variants

Description

138376 bp

Transcription

9090 bp mRNA

Pseudogene

None known

Proteins

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.

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.

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 devils advocate and a reminder that genes dont always read the journals.

Implicated in

Entity name
Development, immunity, tumorigenesis.

Bibliography

Pubmed IDLast YearTitleAuthors
126126392003Mannose 6-phosphate receptors: new twists in the tale.Ghosh P et al
114389902001Mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) variants in American and Japanese populations.Killian JK et al
13232361992Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors.Kornfeld S et al
110816352000Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis.Motyka B et al
128129842003Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions.Sandovici I et al
85954191995Conservation of a maternal-specific methylation signal at the human IGF2R locus.Smrzka OW et al
93387881997Imprinted expression of the Igf2r gene depends on an intronic CpG island.Wutz A et al
92942141997Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis.Yamada T et al
111757802001Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture.Young LE et al

Other Information

Locus ID:

NCBI: 3482
MIM: 147280
HGNC: 5467
Ensembl: ENSG00000197081

Variants:

dbSNP: 3482
ClinVar: 3482
TCGA: ENSG00000197081
COSMIC: IGF2R

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000197081ENST00000356956P11717
ENSG00000197081ENST00000475834S4R328

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
LysosomeKEGGko04142
LysosomeKEGGhsa04142
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Vesicle-mediated transportREACTOMER-HSA-5653656
Membrane TraffickingREACTOMER-HSA-199991
trans-Golgi Network Vesicle BuddingREACTOMER-HSA-199992
Clathrin derived vesicle buddingREACTOMER-HSA-421837
Golgi Associated Vesicle BiogenesisREACTOMER-HSA-432722
Intra-Golgi and retrograde Golgi-to-ER trafficREACTOMER-HSA-6811442
Retrograde transport at the Trans-Golgi-NetworkREACTOMER-HSA-6811440
Clathrin-mediated endocytosisREACTOMER-HSA-8856828
Cargo recognition for clathrin-mediated endocytosisREACTOMER-HSA-8856825
Neutrophil degranulationREACTOMER-HSA-6798695

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
171017782007Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the trafficking of mannose 6-phosphate receptors.81
192400612009Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.75
82676111993Functional polymorphism in the parental imprinting of the human IGF2R gene.57
239848792013Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor.47
188326562009Endothelial progenitor cell homing: prominent role of the IGF2-IGF2R-PLCbeta2 axis.46
150033892004The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system.44
186119742008Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors.44
207340642010A large-scale candidate gene association study of age at menarche and age at natural menopause.38
206738682010A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM).36
186361242008Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma.32

Citation

J Keith Killian

IGF2R (insulin-like growth factor 2 receptor)

Atlas Genet Cytogenet Oncol Haematol. 2004-03-01

Online version: http://atlasgeneticsoncology.org/gene/380/igf2r-(insulin-like-growth-factor-2-receptor)