IGF2R

Identity

Other names	M6P/IGF2R
HGNC	IGF2R
Location	6q25-q27

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

Entity	Development, immunity, tumorigenesis.

External links

	Nomenclature
HGNC	IGF2R   5467
Entrez_Gene	IGF2R  3482  insulin-like growth factor 2 receptor
	Cards
Atlas	IGF2RID380
GeneCards	IGF2R
Ensembl	IGF2R [Search_View]   ENSG00000197081 [Gene_View]
Genatlas	IGF2R
GeneLynx	IGF2R
eGenome	IGF2R
euGene	3482
	Genomic and cartography
GoldenPath	IGF2R  -     chr6:160310121-160447573 +  6q25-q27   [Description]    (hg18-Mar_2006)
Ensembl	IGF2R - 6q25-q27 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	IGF2R
	Gene and transcription
Genbank	AB209668 [ ENTREZ ]
Genbank	J03528 [ ENTREZ ]
Genbank	Y00285 [ ENTREZ ]
RefSeq	NM_000876 [ SRS ]    NM_000876 [ ENTREZ ]
RefSeq	AC_000049 [ SRS ]    AC_000049 [ ENTREZ ]
RefSeq	AC_000138 [ SRS ]    AC_000138 [ ENTREZ ]
RefSeq	NC_000006 [ SRS ]    NC_000006 [ ENTREZ ]
RefSeq	NT_007422 [ SRS ]    NT_007422 [ ENTREZ ]
RefSeq	NW_001838991 [ SRS ]    NW_001838991 [ ENTREZ ]
RefSeq	NW_923184 [ SRS ]    NW_923184 [ ENTREZ ]
AceView	IGF2R AceView - NCBI
Unigene	Hs.487062 [ SRS ]    Hs.487062 [ NCBI ]     HS487062 [ spliceNest ]
Fast-db	16951 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P11717 [ SRS]    P11717 [ EXPASY ]     P11717 [ INTERPRO ]     P11717 [ UNIPROT ]
Prosite	PS00023 FN2_1 [ SRS ]    PS00023 FN2_1 [ Expasy ]
Prosite	PS51092 FN2_2 [ SRS ]    PS51092 FN2_2 [ Expasy ]
Interpro	IPR000479 CIMR [ SRS ]    IPR000479 CIMR [ EBI ]
Interpro	IPR000562 FN_type2_col_bd [ SRS ]    IPR000562 FN_type2_col_bd [ EBI ]
CluSTr	P11717
Pfam	PF00878 CIMR [ SRS ]    PF00878 CIMR [ Sanger ]    pfam00878 [ NCBI-CDD ]
Pfam	PF00040 fn2 [ SRS ]    PF00040 fn2 [ Sanger ]    pfam00040 [ NCBI-CDD ]
Smart	SM00059 FN2 [EMBL]
Prodom	PD000995 FN_Type_II[INRA-Toulouse]
Prodom	P11717 MPRI_HUMAN [ Domain structure ]   P11717 MPRI_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	P11717
PDB	1E6F [ SRS ]    1E6F [ PdbSum ],   1E6F [ IMB ]   1E6F [ RSDB ]
PDB	1GP0 [ SRS ]    1GP0 [ PdbSum ],   1GP0 [ IMB ]   1GP0 [ RSDB ]
PDB	1GP3 [ SRS ]    1GP3 [ PdbSum ],   1GP3 [ IMB ]   1GP3 [ RSDB ]
PDB	1GQB [ SRS ]    1GQB [ PdbSum ],   1GQB [ IMB ]   1GQB [ RSDB ]
PDB	1JWG [ SRS ]    1JWG [ PdbSum ],   1JWG [ IMB ]   1JWG [ RSDB ]
PDB	1LF8 [ SRS ]    1LF8 [ PdbSum ],   1LF8 [ IMB ]   1LF8 [ RSDB ]
PDB	2CNJ [ SRS ]    2CNJ [ PdbSum ],   2CNJ [ IMB ]   2CNJ [ RSDB ]
PDB	2V5N [ SRS ]    2V5N [ PdbSum ],   2V5N [ IMB ]   2V5N [ RSDB ]
PDB	2V5O [ SRS ]    2V5O [ PdbSum ],   2V5O [ IMB ]   2V5O [ RSDB ]
PDB	2V5P [ SRS ]    2V5P [ PdbSum ],   2V5P [ IMB ]   2V5P [ RSDB ]
HPRD	00928
	Protein Interaction databases
DIP	P11717
IntAct	P11717
	Polymorphism : SNP, mutations, diseases
OMIM	147280    [ map ]
GENECLINICS	147280
SNP	IGF2R [dbSNP-NCBI]
SNP	NM_000876 [SNP-NCI]
SNP	IGF2R [GeneSNPs - Utah]  IGF2R] [HGBASE - SRS]
HAPMAP	IGF2R [HAPMAP]
HGMD	IGF2R
	General knowledge
Family Browser	IGF2R [UCSC Family Browser]
SOURCE	NM_000876
SMD	Hs.487062
SAGE	Hs.487062
GO	receptor activity [Amigo]  receptor activity
GO	insulin-like growth factor receptor activity [Amigo]  insulin-like growth factor receptor activity
GO	transporter activity [Amigo]  transporter activity
GO	protein binding [Amigo]  protein binding
GO	insulin-like growth factor binding [Amigo]  insulin-like growth factor binding
GO	nucleus [Amigo]  nucleus
GO	nuclear envelope lumen [Amigo]  nuclear envelope lumen
GO	cytoplasm [Amigo]  cytoplasm
GO	lysosomal membrane [Amigo]  lysosomal membrane
GO	endosome [Amigo]  endosome
GO	integral to plasma membrane [Amigo]  integral to plasma membrane
GO	transport [Amigo]  transport
GO	receptor-mediated endocytosis [Amigo]  receptor-mediated endocytosis
GO	signal transduction [Amigo]  signal transduction
GO	membrane [Amigo]  membrane
GO	trans-Golgi network transport vesicle [Amigo]  trans-Golgi network transport vesicle
PubGene	IGF2R
TreeFam	IGF2R
CTD	3482 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	IGF2R Related clones (RZPD - Berlin)
	PubMed
PubMed	77 Pubmed reference(s) in LocusLink

Bibliography

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

Conservation of a maternal-specific methylation signal at the human IGF2R locus.

Smrzka OW, Fa�� I, St��ger 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

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

Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary.

Killian JK, Nolan CM, Wylie AA, Li T, Vu TH, Hoffman AR, Jirtle RL

Human molecular genetics. 2001 ; 10 (17) : 1721-1728.

PMID 11532981

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

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

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

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

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Last year publications	automatic search in PubMed

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Contributor(s)

Written	03-2004	J Keith Killian

Citation

This paper should be referenced as such :

Killian JK . IGF2R. Atlas Genet Cytogenet Oncol Haematol. March 2004 . URL : http://AtlasGeneticsOncology.org/Genes/IGF2RID380.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:14:31 2008