IGF2R

Official Full Name

insulin like growth factor 2 receptor

Organism

Homo sapiens

GeneID

3482

Background

This gene encodes a receptor for both insulin-like growth factor 2 and mannose 6-phosphate. The binding sites for each ligand are located on different segments of the protein. This receptor has various functions, including in the intracellular trafficking of lysosomal enzymes, the activation of transforming growth factor beta, and the degradation of insulin-like growth factor 2. Mutation or loss of heterozygosity of this gene has been association with risk of hepatocellular carcinoma. The orthologous mouse gene is imprinted and shows exclusive expression from the maternal allele; however, imprinting of the human gene may be polymorphic, as only a minority of individuals showed biased expression from the maternal allele (PMID:8267611). [provided by RefSeq, Nov 2015]

Synonyms

MPR1; MPRI; CD222; CIMPR; M6P-R; MPR300; CI-M6PR; MPR 300; M6P/IGF2R;

Bio Chemical Class

Mannose 6-phosphate receptor

Protein Sequence

MGAAAGRSPHLGPAPARRPQRSLLLLQLLLLVAAPGSTQAQAAPFPELCSYTWEAVDTKNNVLYKINICGSVDIVQCGPSSAVCMHDLKTRTYHSVGDSVLRSATRSLLEFNTTVSCDQQGTNHRVQSSIAFLCGKTLGTPEFVTATECVHYFEWRTTAACKKDIFKANKEVPCYVFDEELRKHDLNPLIKLSGAYLVDDSDPDTSLFINVCRDIDTLRDPGSQLRACPPGTAACLVRGHQAFDVGQPRDGLKLVRKDRLVLSYVREEAGKLDFCDGHSPAVTITFVCPSERREGTIPKLTAKSNCRYEIEWITEYACHRDYLESKTCSLSGEQQDVSIDLTPLAQSGGSSYISDGKEYLFYLNVCGETEIQFCNKKQAAVCQVKKSDTSQVKAAGRYHNQTLRYSDGDLTLIYFGGDECSSGFQRMSVINFECNKTAGNDGKGTPVFTGEVDCTYFFTWDTEYACVKEKEDLLCGATDGKKRYDLSALVRHAEPEQNWEAVDGSQTETEKKHFFINICHRVLQEGKARGCPEDAAVCAVDKNGSKNLGKFISSPMKEKGNIQLSYSDGDDCGHGKKIKTNITLVCKPGDLESAPVLRTSGEGGCFYEFEWHTAAACVLSKTEGENCTVFDSQAGFSFDLSPLTKKNGAYKVETKKYDFYINVCGPVSVSPCQPDSGACQVAKSDEKTWNLGLSNAKLSYYDGMIQLNYRGGTPYNNERHTPRATLITFLCDRDAGVGFPEYQEEDNSTYNFRWYTSYACPEEPLECVVTDPSTLEQYDLSSLAKSEGGLGGNWYAMDNSGEHVTWRKYYINVCRPLNPVPGCNRYASACQMKYEKDQGSFTEVVSISNLGMAKTGPVVEDSGSLLLEYVNGSACTTSDGRQTTYTTRIHLVCSRGRLNSHPIFSLNWECVVSFLWNTEAACPIQTTTDTDQACSIRDPNSGFVFNLNPLNSSQGYNVSGIGKIFMFNVCGTMPVCGTILGKPASGCEAETQTEELKNWKPARPVGIEKSLQLSTEGFITLTYKGPLSAKGTADAFIVRFVCNDDVYSGPLKFLHQDIDSGQGIRNTYFEFETALACVPSPVDCQVTDLAGNEYDLTGLSTVRKPWTAVDTSVDGRKRTFYLSVCNPLPYIPGCQGSAVGSCLVSEGNSWNLGVVQMSPQAAANGSLSIMYVNGDKCGNQRFSTRITFECAQISGSPAFQLQDGCEYVFIWRTVEACPVVRVEGDNCEVKDPRHGNLYDLKPLGLNDTIVSAGEYTYYFRVCGKLSSDVCPTSDKSKVVSSCQEKREPQGFHKVAGLLTQKLTYENGLLKMNFTGGDTCHKVYQRSTAIFFYCDRGTQRPVFLKETSDCSYLFEWRTQYACPPFDLTECSFKDGAGNSFDLSSLSRYSDNWEAITGTGDPEHYLINVCKSLAPQAGTEPCPPEAAACLLGGSKPVNLGRVRDGPQWRDGIIVLKYVDGDLCPDGIRKKSTTIRFTCSESQVNSRPMFISAVEDCEYTFAWPTATACPMKSNEHDDCQVTNPSTGHLFDLSSLSGRAGFTAAYSEKGLVYMSICGENENCPPGVGACFGQTRISVGKANKRLRYVDQVLQLVYKDGSPCPSKSGLSYKSVISFVCRPEARPTNRPMLISLDKQTCTLFFSWHTPLACEQATECSVRNGSSIVDLSPLIHRTGGYEAYDESEDDASDTNPDFYINICQPLNPMHGVPCPAGAAVCKVPIDGPPIDIGRVAGPPILNPIANEIYLNFESSTPCLADKHFNYTSLIAFHCKRGVSMGTPKLLRTSECDFVFEWETPVVCPDEVRMDGCTLTDEQLLYSFNLSSLSTSTFKVTRDSRTYSVGVCTFAVGPEQGGCKDGGVCLLSGTKGASFGRLQSMKLDYRHQDEAVVLSYVNGDRCPPETDDGVPCVFPFIFNGKSYEECIIESRAKLWCSTTADYDRDHEWGFCRHSNSYRTSSIIFKCDEDEDIGRPQVFSEVRGCDVTFEWKTKVVCPPKKLECKFVQKHKTYDLRLLSSLTGSWSLVHNGVSYYINLCQKIYKGPLGCSERASICRRTTTGDVQVLGLVHTQKLGVIGDKVVVTYSKGYPCGGNKTASSVIELTCTKTVGRPAFKRFDIDSCTYYFSWDSRAACAVKPQEVQMVNGTITNPINGKSFSLGDIYFKLFRASGDMRTNGDNYLYEIQLSSITSSRNPACSGANICQVKPNDQHFSRKVGTSDKTKYYLQDGDLDVVFASSSKCGKDKTKSVSSTIFFHCDPLVEDGIPEFSHETADCQYLFSWYTSAVCPLGVGFDSENPGDDGQMHKGLSERSQAVGAVLSLLLVALTCCLLALLLYKKERRETVISKLTTCCRRSSNVSYKYSKVNKEEETDENETEWLMEEIQLPPPRQGKEGQENGHITTKSVKALSSLHGDDQDSEDEVLTIPEVKVHSGRGAGAESSHPVRNAQSNALQEREDDRVGLVRGEKARKGKSSSAQQKTVSSTKLVSFHDDSDEDLLHI

Open

Disease

Fibrosis, Sarcoidosis, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

The IGF2R gene encodes a receptor that has significant roles in various biological processes, particularly in cellular trafficking and regulation. The receptor binds to two distinct ligands: insulin-like growth factor 2 (IGF2) and mannose 6-phosphate (M6P), with each ligand binding to different segments of the protein. This receptor plays a crucial role in the intracellular trafficking of lysosomal enzymes, activation of transforming growth factor beta (TGF-β), and degradation of IGF2. Its dysfunction, either due to mutations or loss of heterozygosity, is associated with an increased risk of hepatocellular carcinoma.

In mammals, the IGF2R gene exhibits a unique feature known as genomic imprinting, where the gene is expressed predominantly from the maternal allele in some individuals. This imprinted expression is highly relevant in the context of diseases and developmental processes, and understanding the mechanisms behind IGF2R's function and regulation is critical to understanding its role in both normal biology and disease progression.

Figure 1 shows IGF2R activation, its interaction with PLAU and latent TGF-beta, leading to TGF-beta activation, MAPK-mediated phosphorylation of TACE/ADAM17, and IGF2R cleavage, with antibody binding sites indicated. Figure 1. IGF2R activation and signaling. (Castro JJ, et al., 2023)

Biological Functions and Mechanisms

The IGF2R receptor performs several critical functions within cells. It mediates the transport of lysosomal enzymes, which are phosphorylated with mannose 6-phosphate (M6P) residues, from the Golgi apparatus to lysosomes. This process is facilitated by the binding of M6P to the receptor, resulting in the formation of a receptor-ligand complex. The complex is then transported to an acidic prelysosomal compartment, where the low pH causes the dissociation of the complex, and the receptor is recycled to the Golgi for subsequent trafficking rounds.

In addition to its role in lysosomal enzyme transport, the IGF2R receptor also plays a pivotal role in regulating the TGF-β signaling pathway, which is essential for immune response modulation. IGF2R has been shown to regulate T-cell coactivation by binding to the DPP4 receptor, thereby contributing to immune cell responses. This regulation is critical in the context of inflammatory and immune diseases.

The receptor also binds IGF2, a peptide growth factor, contributing to the regulation of growth and development. The interaction between IGF2 and IGF2R is significant for maintaining cellular homeostasis, as the receptor helps control the levels of free IGF2 in the circulation by facilitating its clearance from the blood.

IGF2 and Its Impact on Health

Various biological processes include IGF2 itself. With both elements significantly influencing development and metabolism, it has a great deal of similarity with insulin-like growth factor 1 (IGF1). However, the structure and function of these two growth factors differ significantly. Although IGF1 and IGF2 have comparable amino acid sequences, IGF2 features a unique 34-amino-acid E domain called Preptin that works apart from IGF2's regular activities. Preptin is a possible therapeutic target for bone illnesses like osteoporosis as it contains bone-forming qualities and has been demonstrated to increase insulin release.

IGF2 levels in the body are greatest during embryonic development and drop dramatically after delivery. Notwithstanding this drop, IGF2 levels in both adults and children are much greater than those of IGF1. Genetic imprinting also affects the gene's expression; in some tissues, the maternal allele is usually silenced. Regulating growth and cellular activities throughout fetal development depends much on this imprinted expression.

Its link with growth abnormalities is one important aspect of IGF2. Excessive IGF2 expression, for example, has been connected to Beckwith-Wiedemann syndrome (BWS), a disorder marked by fetal overgrowth, higher cancer risk, and early delivery. BWS is characterized by aberrant growth and developmental results caused by a lack of imprinting on the IGF2 gene, which results in overexpression of both alleles.

IGF2R and Imprinting Mechanisms

Being an imprinted gene, the IGF2R gene is expressed in a parent-of-origin-specific way. In humans, the gene is usually expressed from the maternal allele; the paternal allele is silent. A major control tool in fetal development and growth is this imprinted expression. Loss of imprinting (LOI) of the IGF2 gene has been linked to aberrant expression patterns and other developmental anomalies, including BWS.

A complicated and fascinating process called genomic imprinting determines the expression of particular genes by the parent from whom they were inherited. For IGF2, the imprinted expression from the paternal allele guarantees suitable fetal development. Imprinting mistakes cause IGF2 to be overexpressed, which can lead to overgrowth disorders like BWS. Although the effects on human health are substantial, the link between imprinting and illness progression is still under active study.

Furthermore, keeping IGF2 levels in the blood is also greatly influenced by the IGF2R gene. It ensures IGF2 does not go too high by helping to control its clearance. In some cancers, such as non-insulin-secreting ones, the IGF2R receptor may become unbalanced, causing aberrant IGF2 levels and supporting tumor development as well as hypoglycemia.

The IGF2R gene's regulation via imprinting also has implications in male fertility. Studies suggest that IGF2 imprinting defects can influence male reproductive health, and disruptions in imprinting may contribute to idiopathic male infertility. Environmental factors, such as exposure to toxins, can also affect IGF2's imprinting and subsequent reproductive health.

References:

Vecchio I, Tornali C, Bragazzi NL, et al. The Discovery of Insulin: An Important Milestone in the History of Medicine. Front Endocrinol (Lausanne). 2018. 9: 613.
Dulak NC, Temin HM. Multiplication-stimulating activity for chicken embryo fibroblasts from rat liver cell conditioned medium: a family of small polypeptides. J Cell Physiol. 1973. 81(2): 161-70.
Castro JJ, Umana-Perez A, et al. DHA Supplementation during Pregnancy in Women with Obesity Normalizes IGF2R Levels in the Placenta of Male Newborns. Int J Endocrinol. 2023;2023:1515033.

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