Disease relevance of IGF2R

• M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity [1].
• Recently, a high frequency of loss of heterozygosity with concomitant mutations in the remaining allele has been shown to occur at the M6P/IGF2R locus (i.e., 6q26-q27) in both human liver and breast tumors, suggesting that this gene functions as a tumor suppressor [2].
• Together these observations implicate IGF-I as an important factor during the initiation and progression of primary prostate cancer and provide evidence that there is a strong selection against expression of IGF1R and IGF2R in metastatic and androgen-independent disease [3].
• Recently, it was reported in the United States that loss of heterozygosity (LOH) and mutations in exons 27, 28, and 31 of the M6P/IGF2R gene are frequent in hepatocellular carcinomas (HCCs) and adenomas [4].
• M6P/IGF2R is mutated in squamous cell carcinoma of the lung [5].

High impact information on IGF2R

• We now present evidence that this receptor is the cation-independent mannose 6-phosphate/insulin-like growth factor receptor (CI-MPR) [6].
• Significantly, expression of the CI-MPR was essential for cytotoxic T cell-mediated apoptosis of target cells in vitro and for the rejection of allogeneic cells in vivo [6].
• Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours [7].
• To determine whether the cognate genes are also subject to imprinting in humans, we have studied allele-specific expression patterns of insulin-like growth factor 2, IGF2-receptor and H19 in human fetal and adult tissues [8].
• Genomic imprinting and the strange case of the insulin-like growth factor II receptor [9].

Chemical compound and disease context of IGF2R

• IGF-II was weakly related to ponderal index (r = 0.18; P < 0.05) and placental weight (r = 0.18; P < 0.05), and the molar ratio of IGF-II to IGF2R was also related to birth weight (r = 0.15; P < 0.05) [10].
• LDL cholesterol was inversely related to birth weight (r = -0.31, p < 0.05), corrected stature (r = -0.32, p < 0.05), and actual height (r = -0.31, p < 0.05) and directly related to the levels of IGF2R (r = 0.44, p < 0.01) [11].
• BACKGROUND: Loss or mutation of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) has been found in breast cancer [12].
• Failure to detect genetic alteration of the mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) gene in hepatocellular carcinomas in Japan [4].
• We conclude that estradiol down-regulates the Man-6-P/IGF-II receptor in breast cancer cells [13].

Biological context of IGF2R

• Structural analysis identifies the putative IGF-II binding site at one end of the beta-barrel whilst crystal lattice contacts suggest a model for the full-length IGF2R extracellular region [14].
• Thus, dimerization of glycosylated CREG likely presents a bivalent ligand for the M6P/IGF2R [15].
• At the IGF2R DMR, we observed more variability in the allelic methylation ratios over time but also observed familial clustering of abnormal methylation ratios [16].
• The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) forms oligomeric structures important for optimal function in binding and internalization of Man-6-P-bearing extracellular ligands as well as lysosomal biogenesis and growth regulation [17].
• The M6P/IGF2R is a tumor suppressor that functions to control cell growth through interactions with multiple ligands [18].

Anatomical context of IGF2R

• Consistent with the absence of M6P/IGF2R, SCC-VII cells lack dense lysosomes, with the bulk of intracellular acid hydrolases residing in late endosomes/ prelysosomes [19].
• IGF2R, with multiple functions in both normal growth and cancer, was investigated here as a possible USF target in both nontumorigenic and tumorigenic breast cell lines [20].
• These E boxes were found to be essential for IGF2R promoter activity in the nontumorigenic mammary epithelial cell line MCF-10A [20].
• Interestingly, CTSD is transported by IGF2R from the trans Golgi network to the lysosome [21].
• Analysis of IGF2R expression and function suggested that decreased IGF2R expression could partly account for the increased growth of lymph node carcinoma of the prostate (LNCaP) human prostate cancer cells observed with increasing passage in culture [22].

Associations of IGF2R with chemical compounds

• Western blotting analysis revealed that SCC-VII cells are deficient in the 300 kDa mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R), a tumor suppressor with a central role in the intracellular transport of lysosomal enzymes [19].
• The M6P/IGF2R functions in the inactivation of the mitogen IGF2 and in the activation of the growth inhibitor, transforming growth factor beta [2].
• We have mutated residues A54 and L55 of IGF-II in the second A domain helix to arginine (found in the corresponding positions of IGF-I) and measured IGF2R binding [23].
• The Type-2 insulin-like growth factor receptor (IGF2R) is a ubiquitously expressed integral glycoprotein with a molecular mass of 300 kDa [24].
• In addition, suramin inhibited cross-linking of ¿125I¿IGF-II to the type 1 IGF receptor (IGF1R) and type 2 IGF receptor (IGF2R) [25].

Physical interactions of IGF2R

• The remaining allele in 6/11 (55%) LOH patients contained mutations in either the mannose 6-phosphate or the IGF2 binding domain of the M6P/IGF2R [5].
• M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-beta1 [26].
• Thus, analysis of a structure-based mutant of CREG revealed that binding to M6P/IGF2R, while necessary, is not sufficient for CREG-induced growth suppression [15].
• Coimmunoprecipitation assays revealed that soluble recombinant uPAR (suPAR) bound the Man-6-P/IGF2R at two distinct sites, one localized to the amino-terminal end of the Man-6-P/IGF2R extracytoplasmic domain (repeats 1-3) and the other to the more carboxyl-terminal end (repeats 7-9) [27].
• Thus, GGA2 binding to the CI-MPR is important for lysosomal enzyme targeting [28].

Regulatory relationships of IGF2R

• A soluble, circulating form of IGF2R inhibits IGF-II mediated DNA synthesis and may therefore restrain fetal growth [10].
• These studies reveal that CREG inhibits cell growth dependent on the M6P/IGF2R and suggest that interactions between CREG and a well-characterized tumor suppressor may contribute to regulation of proliferation and differentiation in multiple lineages [18].
• A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking [29].
• An immunoglobulin (no. 3637) directed against the rat IGF-II receptor blocked the degradation of [125I]IGF-II added to C6 glial cells, presumably by blocking receptor-mediated internalization [30].

Other interactions of IGF2R

• Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions [16].
• The 5'-flanking sequences of the human IGF2R gene contain multiple, highly conserved E boxes almost identical to the consensus USF DNA-binding sequence [20].
• The IGF2 receptor is a USF2-specific target in nontumorigenic mammary epithelial cells but not in breast cancer cells [20].
• SLC22A2 and SLC22A3, two genes downstream of IGF2R that are imprinted in the mouse, showed no T1D association [31].
• There was no significant difference in the levels of transcripts for IGF1, insulin receptor, or IGF2R between normal and IUGR term placentas [32].

Analytical, diagnostic and therapeutic context of IGF2R

• Two polymorphisms in the 3'-untranslated region of the M6P/IGF2R were used to screen lung tumors for loss of heterozygosity (LOH) by PCR amplification of DNA [5].
• Total RNA from 19 of the 29 patients was utilized to determine a 192 bp insert in the M6P/IGF2R mRNA and expression of this gene by RT-PCR [33].
• DESIGN AND METHODS: The hypothesis was tested in a normal birth cohort (Avon Longitudinal Study of Parents and Children) by genotyping the IGF2R gene gly1619arg polymorphism, which causes a non-conservative amino acid change in the IGF-II binding region, using PCR and restriction fragment length polymorphism analysis [34].
• Sequence analysis indicated a difference in the 3'-untranslated region of M6P/IGF2R between the two cell lines, but no mutation in the M6P-binding domain of the receptor [35].
• METHODS: In total, 43 patients with prostate cancer treated by radical prostatectomy, with archival material available for analysis, were assessed for loss of heterozygosity (LOH) in the M6P/IGF2R gene using six different gene-specific nucleotide polymorphisms [36].

References