Insulin-like growth factor 1 receptor

The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in molecular structure to insulin. IGF-1 plays an important role in growth and continues to have anabolic effects in adults – meaning that it can induce hypertrophy of skeletal muscle and other target tissues. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass. This testifies to the strong growth-promoting effect of this receptor.

IGF1R
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1IGR, 1JQH, 1K3A, 1M7N, 1P4O, 2OJ9, 2ZM3, 3D94, 3F5P, 3I81, 3LVP, 3LW0, 3NW5, 3NW6, 3NW7, 3O23, 3QQU, 4D2R, 4XSS, 5HZN
Identifiers
Aliases	IGF1R, CD221, IGFIR, IGFR, JTK13, insulin like growth factor 1 receptor, Insulin-like growth factor 1，IGF-1R
External IDs	OMIM: 147370 MGI: 96433 HomoloGene: 30997 GeneCards: IGF1R
Gene location (Human) Chr. Chromosome 15 (human)^[1] Band 15q26.3 Start 98,648,539 bp^[1] End 98,964,530 bp^[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)^[2] Band 7 C|7 37.27 cM Start 67,602,575 bp^[2] End 67,883,416 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in caput epididymis corpus epididymis renal medulla saphenous vein lactiferous duct sural nerve bronchial epithelial cell retinal pigment epithelium stromal cell of endometrium seminal vesicula Top expressed in molar ciliary body retinal pigment epithelium conjunctival fornix seminal vesicula pineal gland cumulus cell ascending aorta right lung lobe maxillary prominence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity insulin-like growth factor binding insulin receptor binding insulin binding kinase activity phosphatidylinositol 3-kinase binding insulin-like growth factor-activated receptor activity protein binding identical protein binding transmembrane receptor protein tyrosine kinase activity insulin receptor substrate binding protein tyrosine kinase activity ATP binding insulin-like growth factor I binding insulin-activated receptor activity Cellular component integral component of membrane membrane intracellular membrane-bounded organelle receptor complex plasma membrane integral component of plasma membrane alphav-beta3 integrin-IGF-1-IGF1R complex insulin receptor complex axon Biological process insulin receptor signaling pathway insulin-like growth factor receptor signaling pathway phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway positive regulation of cell migration negative regulation of apoptotic process protein tetramerization positive regulation of DNA replication protein phosphorylation regulation of JNK cascade immune response positive regulation of cell population proliferation peptidyl-tyrosine autophosphorylation protein autophosphorylation phosphatidylinositol 3-kinase signaling phosphatidylinositol-mediated signaling signal transduction positive regulation of phosphatidylinositol 3-kinase signaling glucose homeostasis positive regulation of protein-containing complex disassembly positive regulation of MAPK cascade anatomical structure development positive regulation of protein kinase B signaling cellular response to glucose stimulus dendritic spine maintenance amyloid-beta clearance positive regulation of cold-induced thermogenesis cellular response to amyloid-beta Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3480 16001 Ensembl ENSG00000140443 ENSMUSG00000005533 UniProt P08069 Q60751 RefSeq (mRNA) NM_000875 NM_001291858 NM_152452 NM_010513 RefSeq (protein) NP_000866 NP_001278787 NP_034643 Location (UCSC) Chr 15: 98.65 – 98.96 Mb Chr 7: 67.6 – 67.88 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

 

Schematic diagram of the IGF-1R structure

Two alpha subunits and two beta subunits make up the IGF-1 receptor. Both the α and β subunits are synthesized from a single mRNA precursor. The precursor is then glycosylated, proteolytically cleaved, and crosslinked by cysteine bonds to form a functional transmembrane αβ chain.^[5] The α chains are located extracellularly, while the β subunit spans the membrane and is responsible for intracellular signal transduction upon ligand stimulation. The mature IGF-1R has a molecular weight of approximately 320 kDa.^citation? The receptor is a member of a family which consists of the insulin receptor and the IGF-2R (and their respective ligands IGF-1 and IGF-2), along with several IGF-binding proteins.

IGF-1R and the insulin receptor both have a binding site for ATP, which is used to provide the phosphates for autophosphorylation. There is a 60% homology between IGF-1R and the insulin receptor. The structures of the autophosphorylation complexes of tyrosine residues 1165 and 1166 have been identified within crystals of the IGF1R kinase domain.^[6]

In response to ligand binding, the α chains induce the tyrosine autophosphorylation of the β chains. This event triggers a cascade of intracellular signaling that, while cell type-specific, often promotes cell survival and cell proliferation.^[7][8]

Family members

Tyrosine kinase receptors, including the IGF-1 receptor, mediate their activity by causing the addition of a phosphate groups to particular tyrosines on certain proteins within a cell. This addition of phosphate induces what are called "cell signaling" cascades - and the usual result of activation of the IGF-1 receptor is survival and proliferation in mitosis-competent cells, and growth (hypertrophy) in tissues such as skeletal muscle and cardiac muscle.

Function

Embryonic development

During embryonic development, the IGF-1R pathway is involved with the developing limb buds.

Lactation

The IGFR signalling pathway is of critical importance during normal development of mammary gland tissue during pregnancy and lactation. During pregnancy, there is intense proliferation of epithelial cells which form the duct and gland tissue. Following weaning, the cells undergo apoptosis and all the tissue is destroyed. Several growth factors and hormones are involved in this overall process, and IGF-1R is believed to have roles in the differentiation of the cells and a key role in inhibiting apoptosis until weaning is complete.

Insulin signaling

IGF-1 binds to at least two cell surface receptors: the IGF1 Receptor (IGFR), and the insulin receptor. The IGF-1 receptor seems to be the "physiologic" receptor—it binds IGF-1 at significantly higher affinity than it binds insulin.^[9] Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase—meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 10% the potency of insulin. Part of this signaling may be via IGF1R/insulin receptor heterodimers (the reason for the confusion is that binding studies show that IGF-1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF-1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia).

Aging

Studies in female mice have shown that both supraoptic nucleus (SON) and paraventricular nucleus (PVN) lose approximately one-third of IGF-1R immunoreactive cells with normal aging. Also, old calorically restricted (CR) mice lost higher numbers of IGF-1R non-immunoreactive cells while maintaining similar counts of IGF-1R immunoreactive cells in comparison to old-Al mice. Consequently, old-CR mice show a higher percentage of IGF-1R immunoreactive cells, reflecting increased hypothalamic sensitivity to IGF-1 in comparison to normally aging mice.^[10][11]

Craniosynostosis

Mutations in IGF1R have been associated with craniosynostosis.^[12]

Body size

IGF-1R has been shown to have a significant effect on body size in small dog breeds.^[13] A "nonsynonymous SNP at chr3:44,706,389 that changes a highly conserved arginine at amino acid 204 to histidine" is associated with particularly tiny body size. "This mutation is predicted to prevent formation of several hydrogen bonds within the cysteine-rich domain of the receptor’s ligand-binding extracellular subunit. Nine of 13 tiny dog breeds carry the mutation and many dogs are homozygous for it." Smaller individuals within several small and medium-sized breeds were shown to carry this mutation as well.

Mice carrying only one functional copy of IGF-1R are normal, but exhibit a ~15% decrease in body mass. IGF-1R has also been shown to regulate body size in dogs. A mutated version of this gene is found in a number of small dog breeds.^[13]

Gene inactivation/deletion

Deletion of the IGF-1 receptor gene in mice results in lethality during early embryonic development, and for this reason, IGF-1 insensitivity, unlike the case of growth hormone (GH) insensitivity (Laron syndrome), is not observed in the human population.^[14]

Clinical significance

Cancer

The IGF-1R is implicated in several cancers,^[15][16] including breast, prostate, and lung cancers. In some instances its anti-apoptotic properties allow cancerous cells to resist the cytotoxic properties of chemotherapeutic drugs or radiotherapy. In breast cancer, where EGFR inhibitors such as erlotinib are being used to inhibit the EGFR signaling pathway, IGF-1R confers resistance by forming one half of a heterodimer (see the description of EGFR signal transduction in the erlotinib page), allowing EGFR signaling to resume in the presence of a suitable inhibitor. This process is referred to as crosstalk between EGFR and IGF-1R. It is further implicated in breast cancer by increasing the metastatic potential of the original tumour by conferring the ability to promote vascularisation.

Increased levels of the IGF-IR are expressed in the majority of primary and metastatic prostate cancer patient tumors.^[17] Evidence suggests that IGF-IR signaling is required for survival and growth when prostate cancer cells progress to androgen independence.^[18] In addition, when immortalized prostate cancer cells mimicking advanced disease are treated with the IGF-1R ligand, IGF-1, the cells become more motile.^[19] Members of the IGF receptor family and their ligands also seem to be involved in the carcinogenesis of mammary tumors of dogs.^[20][21] IGF1R is amplified in several cancer types based on analysis of TCGA data, and gene amplification could be one mechanism for overexpression of IGF1R in cancer.^[22]

Lung cancer cells stimulated using glucocorticoids were induced into a reversible dormancy state which was dependent on the IGF-1R and its accompanying survival signaling pathways.^[23]

Inhibitors

Due to the similarity of the structures of IGF-1R and the insulin receptor (IR), especially in the regions of the ATP binding site and tyrosine kinase regions, synthesising selective inhibitors of IGF-1R is difficult. Prominent in current research are three main classes of inhibitor:

1. Tyrphostins such as AG538^[24] and AG1024. These are in early pre-clinical testing. They are not thought to be ATP-competitive, although they are when used in EGFR as described in QSAR studies. These show some selectivity towards IGF-1R over IR.
2. Pyrrolo(2,3-d)-pyrimidine derivatives such as NVP-AEW541, invented by Novartis, which show far greater (100 fold) selectivity towards IGF-1R over IR.^[25]
3. Monoclonal antibodies are probably the most specific and promising therapeutic compounds. Teprotumumab is a novel therapy showing significant benefit for Thyroid Eye Disease.

Interactions

Insulin-like growth factor 1 receptor has been shown to interact with:

• ARHGEF12,^[26]
• C-src tyrosine kinase,^[27]
• Cbl gene,^[28]
• EHD1,^[29]
• GRB10,^{[30][31][32][33]}
• IRS1,^[31][34][35]
• Mdm2,^[28]
• NEDD4,^[28][30]
• PIK3R3,^[36]
• PTPN11,^[34][37]
• RAS p21 protein activator 1,^[37]
• SHC1^[31][35][38]
• SOCS2,^[39]
• SOCS3,^[40] and
• YWHAE.^[41]

Regulation

There is evidence to suggest that IGF1R is negatively regulated by the microRNA miR-7.^[42]

See also

• Hypothalamic–pituitary–somatic axis
• Insulin receptor
• Linsitinib, an inhibitor of IGF-1R in clinical trials for cancer treatment

References

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2. GRCm38: Ensembl release 89: ENSMUSG00000005533 - Ensembl, May 2017
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Further reading

• Benito M, Valverde AM, Lorenzo M (May 1996). "IGF-I: a mitogen also involved in differentiation processes in mammalian cells". The International Journal of Biochemistry & Cell Biology. 28 (5): 499–510. doi:10.1016/1357-2725(95)00168-9. PMID 8697095.
• Butler AA, Yakar S, Gewolb IH, Karas M, Okubo Y, LeRoith D (September 1998). "Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology". Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. 121 (1): 19–26. doi:10.1016/S0305-0491(98)10106-2. PMID 9972281.
• Zhang X, Yee D (2001). "Tyrosine kinase signalling in breast cancer: insulin-like growth factors and their receptors in breast cancer". Breast Cancer Research. 2 (3): 170–5. doi:10.1186/bcr50. PMC 138771. PMID 11250706.
• Gross JM, Yee D (December 2003). "The type-1 insulin-like growth factor receptor tyrosine kinase and breast cancer: biology and therapeutic relevance". Cancer and Metastasis Reviews. 22 (4): 327–36. doi:10.1023/A:1023720928680. PMID 12884909. S2CID 35963688.
• Adams TE, McKern NM, Ward CW (June 2004). "Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor". Growth Factors. 22 (2): 89–95. doi:10.1080/08977190410001700998. PMID 15253384. S2CID 86844427.
• Surmacz E, Bartucci M (September 2004). "Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer". Journal of Experimental & Clinical Cancer Research. 23 (3): 385–94. PMID 15595626.
• Wood AW, Duan C, Bern HA (2005). Insulin-like growth factor signaling in fish. International Review of Cytology. Vol. 243. pp. 215–85. doi:10.1016/S0074-7696(05)43004-1. ISBN 978-0-12-364647-7. PMID 15797461.
• Sarfstein R, Maor S, Reizner N, Abramovitch S, Werner H (June 2006). "Transcriptional regulation of the insulin-like growth factor-I receptor gene in breast cancer". Molecular and Cellular Endocrinology. 252 (1–2): 241–6. doi:10.1016/j.mce.2006.03.018. PMID 16647191. S2CID 24895685.

External links

• IGF-1+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P08069 (Insulin-like growth factor 1 receptor) at the PDBe-KB.