Alternative titles; symbols
HGNC Approved Gene Symbol: IGF2R
Cytogenetic location: 6q25.3 Genomic coordinates (GRCh38): 6:159,969,082-160,111,504 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q25.3 | Hepatocellular carcinoma, somatic | 114550 | 3 |
IGF2R is a multifunctional receptor that possesses binding sites for diverse ligands, including insulin-like growth factor II (IGF2; 147470), retinoic acid, TGF-beta (TGFB1; 190180), urokinase-type plasminogen activator receptor (UPAR, or PLAUR; 173391), and mannose-6-phosphate (M6P), a modification characteristic of lysosomal enzymes. IGF2R plays major roles in controlling IGF signaling by directing IGF2 to lysosomes, in targeting lysosomal enzymes to lysosomes, and in recycling lysosomal enzymes from the plasma membrane (summary by Killian and Jirtle, 1999).
Oshima et al. (1988) cloned and sequenced the full-length cDNA for MPRI, which encodes a protein of 2,491 amino acids. The amino acid sequence includes a putative signal sequence of 40 amino acids, an extracytoplasmic domain consisting of 15 homologous repeat sequences of 134 to 167 amino acids, a transmembrane region of 23 amino acids, and a cytoplasmic domain of 164 amino acids. The predicted molecular mass was greater than 270 kD. On comparison to the reported structure of IGF2R (Morgan et al., 1987), MPRI was found to show 99.8% identity at the nucleotide level and 99.4% identity at the amino acid level. By cDNA sequencing, Laureys et al. (1988) showed that the cation-independent mannose 6-phosphate receptor and IGF2 receptor are identical.
Szebeni and Rotwein (1994) cloned and characterized the mouse Igf2r gene. It encodes a predicted protein of 2,482 amino acids.
Insulin-like growth factor II (147470) is a polypeptide hormone with structural homologies to insulin (INS; 176730) and IGF I (IGF1; 147440). Although IGF II can stimulate a broad range of biologic responses in isolated cells, these responses appear to be mediated by the insulin and IGF I receptors (147670 and 147370, respectively). The receptor for IGF II was found to be the receptor for mannose 6-phosphate, which is implicated in targeting of lysosomal enzymes (MacDonald et al., 1988; Roth, 1988; Tong et al., 1988). Purified human and rat IGF2 receptors interact with antibodies to the mannose 6-phosphate receptor and with mannose 6-phosphate.
Waheed et al. (1988) showed that the M6P and IGF2 binding sites are located on different segments of the receptor.
Kiess et al. (1988) presented biochemical evidence that the IGF2 receptor and the cation-independent mannose 6-phosphate receptor are the same protein, but that the binding sites for the 2 ligands are distinct. In its guise as a mannose 6-phosphate receptor, the IGF2 receptor binds mannose 6-phosphate residues on lysosomal enzymes and transports them into lysosomes (Kornfeld and Mellman, 1989).
The serine proteinase granzyme B (GZMB; 123910) is crucial for the rapid induction of target cell apoptosis by cytotoxic T cells. GZMB enters cells in a perforin-independent manner, predicting the existence of a cell surface receptor(s). Motyka et al. (2000) presented evidence that this receptor is IGF2R. Inhibition of the GZMB-IGF2R interaction prevented GZMB cell surface binding, uptake, and the induction of apoptosis. Significantly, expression of IGF2R was essential for cytotoxic T cell-mediated apoptosis of target cells in vitro and for the rejection of allogeneic cells in vivo.
The cytosolic tails of both the cation-independent and the cation-dependent (154540) mannose 6-phosphate receptors contain acidic cluster-dileucine signals that direct sorting from the trans-Golgi network to the endosomal-lysosomal system. Puertollano et al. (2001) found that these signals bind to the VHS domain of the Golgi-localized, gamma-ear-containing, ARF-binding proteins (GGA1, 606004; GGA2, 606005; GGA3, 606006). The receptors and the GGAs left the trans-Golgi network on the same tubulovesicular carriers. A dominant-negative GGA mutant blocked exit of the receptors from the trans-Golgi network. Puertollano et al. (2001) concluded that the GGAs appear to mediate sorting of the mannose 6-phosphate receptors to the trans-Golgi network.
Zhu et al. (2001) found that the VHS domain of GGA2 binds the acidic cluster-dileucine motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor. Receptors with mutations in this motif were defective in lysosomal enzyme sorting. The hinge domain of GGA2 bound clathrin, suggesting that GGA2 could be a link between cargo molecules and clathrin-coated vesicle assembly. Thus, Zhu et al. (2001) concluded that GGA2 binding to the cation-independent mannose 6-phosphate receptor is important for lysosomal enzyme targeting.
Using immunoblot and confocal microscopy analyses, MacDonald et al. (2014) demonstrated that depletion of USP8 (603158) in HeLa cells affected retromer-dependent shuttling of cation-independent M6PR between the sorting endosome and biosynthetic pathway, resulting in a steady-state redistribution of cation-independent M6PR from the trans-Golgi network to endosomal compartments. This redistribution led to a defect in sorting of lysosomal enzymes, as shown by increased levels of unprocessed cathepsin D (CTSD; 116840) secreted from cells. Normal receptor distribution was restored by expression of small interfering RNA-resistant USP8, but not by expression of catalytically inactive USP8 or truncated USP8 mutants lacking the domain required for endosomal localization. MacDonald et al. (2014) proposed that the effects of USP8 depletion may be due to loss of ESCRT-0 components that associate with the retromer components VPS35 (601501) and SNX1 (601272). They suggested that failure to efficiently deliver lysosomal enzymes may also contribute to the observed block in receptor tyrosine kinase degradation.
Imprinting of IGF2R
Mouse embryos produce transcripts of the Igf2r gene from the maternal chromosome but not from the paternal. This could explain why mice that are heterozygous for deletions of the locus develop normally if their paternal allele is missing but die during early development if the maternal allele is missing. Studies in transgenic mice (Barlow et al., 1991) showed parental imprinting, i.e., monoallelic expression, of the Igf2r gene. It is probably no coincidence that the Igf2 gene and the Igf2r gene are oppositely imprinted in mouse (DeChiara et al., 1991). Haig and Graham (1991) proposed that the oppositely imprinted genes function to control the ultimately adverse effects of excessive production of Igf2 from the maternal allele. The suggestion is based on the model of Haig and Westoby (1989), which proposed that the evolution of genomic imprinting is expected in organisms that have both a breeding system in which females carry offspring by more than one male during their life span and a system of parental care in which offspring receive most of their postfertilization nutrients from 1 parent (usually the mother) and thus compete with offspring fathered by other males. Strictly, imprinting is possible whenever an individual's interactions are asymmetric with respect to maternal- and paternal-side relatives.
Using allele-specific primers and parallel amplification of maternal and fetal DNA, Kalscheuer et al. (1993) determined that both maternal and paternal IGF2R alleles were expressed in all human fetal tissues examined and at all developmental stages examined. They concluded that the IGF2R gene escapes imprinting in humans.
Xu et al. (1993) found that both parental IGF2R alleles were expressed in 4 term placentae and in placenta and lung from 7 of 10 fetuses. Of the remaining 3 fetuses, 2 expressed only the maternal copy, and the third showed partial repression of the paternal allele. In adult blood cell samples, 13 of 14 heterozygotes expressed both alleles, and 1 showed partial repression of 1 allele. Xu et al. (1993) concluded that imprinting at the IGF2R locus is a polymorphic trait in humans.
Although in mice the Igf2r gene is maternally imprinted (Barlow et al., 1991), in humans imprinting appears to be a polymorphic trait (Xu et al., 1993; Kalscheuer et al., 1993; Ogawa et al., 1993). Thus, mice and any humans who are imprinted may have an increased susceptibility to hepatocellular carcinoma, since only 1 mutation would be required to render the gene inactive. De Souza et al. (1995) noted that, since the IGF2R protein is normally present in circulation, mutant receptors in plasma might be helpful in liver tumor detection. Furthermore, they stated that mutated receptors on the plasma membrane of liver tumor cells might provide a surface antigen for the targeting of both therapeutic and diagnostic agents to liver tumors.
Smrzka et al. (1995) found that the intronic CpG island of human IGF2R was methylated in 11 individuals. Analysis in 1 informative family showed that the methylation was specific to the maternal allele, similar to observations in the mouse Igf2r gene. However, unlike the monoallelic expression observed in mouse, only 1 of 70 lymphoblastoid cell lines showed monoallelic IGF2R expression. Smrzka et al. (1995) concluded that the intronic CpG islands of both mouse and human IGF2R are methylated following maternal, but not paternal, transmittance, but this methylation mark does not correlate with allele-specific expression.
By examining the methylation status of genomic DNA from human blood, liver, and placenta, Riesewijk et al. (1996) found that, like mouse Igf2r, the intronic CpG island of human IGF2R was hypermethylated on the maternal allele. However, unlike mouse Igf2r, the upstream CpG island of human IGF2R was completely unmethylated on both parental chromosomes.
Livestock cloning and in vitro embryo culture have been adversely affected by the exceptional size of some resulting lambs and calves. Multiple abnormalities associated with 'large offspring syndrome' (LOS) limit application of these technologies. Similar fetal overgrowth in humans and mice can result from altered expression of several imprinted genes that are expressed only from 1 parental allele, including IGF2R. Cloning or nonphysiologic embryo culture environments may result in inappropriate epigenetic modification of imprinted genes during early embryogenesis, when many allele-specific imprints are established or maintained. Young et al. (2001) demonstrated reduced fetal methylation and expression of sheep Igf2r, suggesting that preimplantation embryo procedures may be vulnerable to epigenetic alterations in imprinted genes. This highlighted the potential benefits of epigenetic diagnostic screening in developing embryo procedures.
In mouse, a bidirectional silencer for a 400-kb region that contains 3 imprinted, maternally expressed protein-coding genes (IGF2R; SLC22A2, 602608; SLC22A3, 604842) has been shown by targeted deletion to be located in a sequence of 3.7 kb, which also contains the promoter for the imprinted, paternally expressed noncoding RNA Air (AIRN; 604893). Expression of Air is correlated with repression of all 3 genes on the paternal allele; however, Air RNA overlaps just 1 of these genes in an antisense orientation. By inserting a polyadenylation signal that truncated 96% of the RNA transcript, Sleutels et al. (2002) demonstrated that Air RNA is required for silencing. The truncated Air allele maintained imprinted expression and methylation of the Air promoter, but showed complete loss of silencing of the Igf2r/Slc22a2/Slc22a3 gene cluster on the paternal chromosome. Sleutels et al. (2002) concluded that noncoding RNAs have an active role in genomic imprinting.
Both the mouse and human IGF2R genes contain differentially methylated regions (DMRs) in the upstream promoter region (DMR1) and within intron 2 (DMR2), which includes the promoter for the antisense transcript, AIR. Imprinting of mouse Igf2r depends on DMR2 and the presence of Air. However, biallelic expression of Igf2r in mouse brain occurs despite the presence of Air, and biallelic expression of human IGF2R in peripheral tissues occurs despite the presence of DMR2. Vu et al. (2004) examined histone modifications throughout mouse and human IGF2R using chromatin immunoprecipitation assays and quantitative real-time PCR. Methylation of lys4 and lys9 of histone H3 in the promoter regions marked the active and silenced alleles, respectively. While both di- and trimethyl lys4 marked the active Igf2r and the active Air allele in mouse, trimethyl lys9 but not dimethyl lys9 marked the suppressed Air allele. Enrichment of parental allele-specific histone modifications in the promoter region, rather than the presence of DNA methylation or antisense transcription, correctly identified the tissue- and species-specific imprinting status of IGF2R. Biallelic expression of human IGF2R in fetal skin cells appeared to be controlled by histone modification at DMR1 only and was independent of methylation at DMR2. No AIR expression was detected in human.
In murine glial cells and fibroblasts, Yamasaki et al. (2005) found that Igf2r was maternally expressed and that Air was paternally expressed. In murine primary cultured neurons, Igf2r was biallelically expressed, and Air was not expressed. In DMR2, which includes the Air promoter, allele-specific DNA methylation, differential H3 and H4 acetylation, and H3K4 and K9 dimethylation were maintained in each cultured cell type. In DMR1, which includes the Igf2r promoter, maternal allele-specific DNA hypomethylation, histones H3 and H4 acetylation, and H3K4 dimethylation were apparent in glial cells and fibroblasts. However, in neurons, biallelic DNA hypomethylation and biallelic histones H3 and H4 acetylation and H3K4 dimethylation were detected. Yamasaki et al. (2005) concluded that lack of reciprocal imprinting of Igf2r and Air in the brain may result from neuron-specific relaxation of Igf2r imprinting associated with neuron-specific histone modifications in DMR1 and lack of Air expression.
Mammalian imprinted genes often cluster with long noncoding (lnc) RNAs. Three lncRNAs that induce parental-specific silencing show hallmarks indicating that their transcription is more important than their product. To test whether Airn (AIRN; 604893) transcription or product silences the Igf2r gene, Latos et al. (2012) shortened the endogenous lncRNA to different lengths. The results excluded a role for spliced and unspliced Airn lncRNA products and for Airn nuclear size and location in silencing Igf2r. Instead, silencing required only Airn transcriptional overlap of the Igf2r promoter, which interferes with RNA polymerase II recruitment in the absence of repressive chromatin. Such a repressor function for lncRNA transcriptional overlap reveals a gene silencing mechanism that may be widespread in the mammalian genome, given the abundance of lncRNA transcripts.
Killian and Jirtle (1999) determined that the IGF2R gene contains 48 exons and spans about 136 kb.
Smrzka et al. (1995) determined that the promoter regions of the mouse and human IGF2R genes are located within CpG islands that lack TATA or CAAT boxes. Several regulatory elements are conserved in mouse and human, including 3 E boxes and several GC boxes. Intron 2 of the IGF2R gene contains a second CpG island in both mouse and human.
Laureys et al. (1988) mapped the human IGF2R gene to chromosome 6q25-q27 using cloned cDNAs to probe Southern blots of somatic cell hybrid DNA and for in situ chromosomal hybridization. By fluorescence in situ hybridization, Rao et al. (1994) narrowed the assignment of the IGF2R gene to chromosome 6q26.
Acquati et al. (1994) described a 2-Mb YAC from the telomeric region of chromosome 6q containing the plasminogen-apolipoprotein(a) gene family at its centromeric end and the IGF2R gene at the telomeric end. About 350 kb separated IGF2R from the nearest member of the PLG/LPA cluster of genes. Barlow et al. (1991) mapped the mouse Igf2r gene to the T-associated maternal effect locus (Tme) on chromosome 17.
Crystal Structure
Placental development and genomic imprinting coevolved with parental conflict over resource distribution to mammalian offspring. The imprinted genes IGF2 and IGF2R code for the growth promoter insulin-like growth factor-2 (IGF2) and its inhibitor, mannose 6-phosphate (M6P)/IGF2 receptor (IGF2R), respectively. M6P/IGF2R of birds and fish do not recognize IGF2. In monotremes, which lack imprinting, IGF2 specifically bound M6P/IGF2R via a hydrophobic CD loop. Williams et al. (2012) showed that the DNA coding the CD loop in monotremes functions as an exon splice enhancer (ESE) and that structural evolution of binding site loops (AB, HI, FG) improved therian IGF2 affinity. Williams et al. (2012) proposed that ESE evolution led to the fortuitous acquisition of IGF2 binding by M6P/IGF2R that drew IGF2R into parental conflict; subsequent imprinting may then have accelerated affinity maturation.
The mannose 6-phosphate/insulin-like growth factor II receptor functions in the intracellular trafficking of lysosomal enzymes, the activation of the potent growth inhibitor, transforming growth factor beta, and the degradation of IGF2, a mitogen often overproduced in tumors. De Souza et al. (1995) demonstrated that 70% of human hepatocellular tumors have loss of heterozygosity (LOH) at the M6P/IGF2R locus at 6q26. In a separate report, De Souza et al. (1995) described a mutation screen that identified point mutations in the remaining allele of 25% of human hepatocellular carcinomas with LOH. One mutation created an alternative splice site within an intron (corresponding to intron 40 in mouse) and resulted in a truncated receptor; 2 others (147280.0001, 147280.0002) gave rise to significant amino acid substitutions. These mutations provided evidence to the authors that the M6P/IGF2R gene functions as a tumor suppressor in human liver carcinogenesis.
Souza et al. (1996) reported that the IGF2R gene contains a number of microsatellite repeats within its coding sequence. They demonstrated microsatellite instability in this gene in 12 of 92 gastrointestinal tumors studied which were replication/repair error-positive. Mutations occurred in 6 of the poorly differentiated tumors. They noted an anticorrespondence of IGF2R and TGFBR2 (190182) mutations. Of 31 gastrointestinal lesions studied with IGF2R or TGFBR2 mutations, 90% (28) contained mutations in one or the other, but not both, of these genes. Souza et al. (1996) demonstrated that all but 1 of the mutations occurred within an 8-polydeoxyguanine tract spanning nucleotides 4089-4096 of the IGF2R coding sequence. In 1 case of gastric adenocarcinoma, mutation occurred in a polyCT tract spanning nucleotides 6169-6180. These mutations all comprised 1- or 2-bp deletions or insertions within the microsatellite region, causing frameshifts and premature stop codons downstream. Souza et al. (1996) noted that the TGFBR2 gene is also subject to microsatellite instability within its coding region. They noted further that IGF2R and TGFBR2 genes comprise serial points in the same tumorigenesis pathway, since mutation of either gene alone occurred in 90% of the gastrointestinal tumors that they analyzed.
To facilitate genetic analyses of the imprint status of human M6P/IGF2R and loss of heterozygosity at this locus in cancer, Killian et al. (2001) screened American and Japanese populations for M6P/IGF2R single nucleotide polymorphisms (SNPs). They identified 9 novel intragenic SNPs and 3 amino acid variants in the ligand-binding domains of M6P/IGF2R that may be under selection in humans.
Sandovici et al. (2003) examined allelic methylation ratios at differentially methylated regions (DMRs) within the IGF2/H19 (103280) and IGF2R loci in a panel of 48 3-generation families. There was familial clustering of individuals with abnormal methylation ratios at the IGF2/H19 DMR, as well as stability of this trait over a period of nearly 2 decades, consistent with the possibility that constitutional loss of imprinting (LOI) at this locus may be due largely to genetic factors. At the IGF2R DMR, more variability in the allelic methylation ratios was observed over time, but there was also familial clustering of abnormal methylation ratios. Sandovici et al. (2003) concluded that shared genetic factors may be responsible for a major fraction of interindividual variability in parental origin-dependent epigenetic modifications; however, temporal changes also occur in isolated cases, as well as within multiple individuals in the same family, indicating that environmental factors may also play a role.
To determine whether paternal expression of the Igf2r gene is necessary for early development in the mouse, Lau et al. (1994) derived mice in which the gene had been disrupted by targeted mutagenesis in embryonic stem (ES) cells with the subsequent introduction of the mutation into the germline of mice. Lau et al. (1994) found that murine embryos that inherit a nonfunctional Igf2r gene from their father are viable and develop normally into adults; however, most mice inheriting the same mutated allele from their mothers die around the time of birth as a consequence of major cardiac abnormalities. The mice that inherit the mutant allele from their mothers do not express Igf2r in their tissues, are 25 to 30% larger than their normal sibs, have elevated levels of circulating IGF2 and IGF-binding proteins, and exhibit a slight kink in the tail. The findings of overgrowth may support the suggestion that relaxation of maternal imprinting of IGF2 plays a role in the features of Beckwith-Wiedemann syndrome (130650) (Feinberg, 1993).
De Souza et al. (1995) found a C-to-A transversion in 1 allele of the IGF2R gene creating a gly1449-to-val amino acid substitution in the gene product. This mutation was found in a tumor which showed deletion of the other allele as judged by loss of heterozygosity (LOH).
De Souza et al. (1995) found a G-to-A transition in 1 allele of the IGF2R gene creating a gly1464-to-glu amino acid substitution in the gene product. This mutation was found in a tumor which showed deletion of the other allele as judged by loss of heterozygosity (LOH).
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