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 67,952,827 bp[2] End 68,233,668 bp[2]
RNA expression pattern 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 • GO:0001948 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 • cell 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 proliferation • inactivation of MAPKK activity • peptidyl-tyrosine autophosphorylation • autophosphorylation • phosphatidylinositol 3-kinase signaling • phosphatidylinositol-mediated signaling • signal transduction • positive regulation of phosphatidylinositol 3-kinase signaling • glucose homeostasis • positive regulation of protein 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: 67.95 – 68.23 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.

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

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.

Function

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 0.1x 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 IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 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]

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[23] 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.[24]
3. Monoclonal antibodies are probably the most specific and promising therapeutic compounds. Those currently undergoing trials include figitumumab.

Interactions

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

• ARHGEF12,[25]
• C-src tyrosine kinase,[26]
• Cbl gene,[27]
• EHD1,[28]
• GRB10,[29][30][31][32]
• IRS1,[30][33][34]
• Mdm2,[27]
• NEDD4,[27][29]
• PIK3R3,[35]
• PTPN11,[33][36]
• RAS p21 protein activator 1,[36]
• SHC1[30][34][37]
• SOCS2,[38]
• SOCS3,[39] and
• YWHAE.[40]

Regulation

There is evidence to suggest that IGF1R is negatively regulated by the microRNA miR-7.[41]

See also

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

References

1. GRCh38: Ensembl release 89: ENSG00000140443 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000005533 - Ensembl, May 2017
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8. LeRoith D, Werner H, Beitner-Johnson D, Roberts CT (April 1995). "Molecular and cellular aspects of the insulin-like growth factor I receptor". Endocrine Reviews. 16 (2): 143–63. doi:10.1210/edrv-16-2-143. PMID 7540132.
9. Hawsawi Y, El-Gendy R, Twelves C, Speirs V, Beattie J (December 2013). "Insulin-like growth factor - oestradiol crosstalk and mammary gland tumourigenesis". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1836 (2): 345–53. doi:10.1016/j.bbcan.2013.10.005. PMID 24189571.
10. Saeed O, Yaghmaie F, Garan SA, Gouw AM, Voelker MA, Sternberg H, Timiras PS (February 2007). "Insulin-like growth factor-1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice". International Journal of Developmental Neuroscience. 25 (1): 23–8. doi:10.1016/j.ijdevneu.2006.11.004. PMID 17194562.
11. Yaghmaie F, Saeed O, Garan SA, Voelker MA, Gouw AM, Freitag W, Sternberg H, Timiras PS (November 2006). "Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice". International Journal of Developmental Neuroscience. 24 (7): 431–6. doi:10.1016/j.ijdevneu.2006.08.008. PMID 17034982.
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15. Warshamana-Greene GS, Litz J, Buchdunger E, García-Echeverría C, Hofmann F, Krystal GW (February 2005). "The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy". Clinical Cancer Research. 11 (4): 1563–71. doi:10.1158/1078-0432.CCR-04-1544. PMID 15746061.
16. Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI (December 2004). "Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells". Endocrine-Related Cancer. 11 (4): 793–814. doi:10.1677/erc.1.00799. PMID 15613453.
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21. Klopfleisch R, Lenze D, Hummel M, Gruber AD (November 2010). "Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles". BMC Cancer. 10: 618. doi:10.1186/1471-2407-10-618. PMC 2994823. PMID 21062462.
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24. http://www.targeting-the-kinome.org/images/Garcia-Echeverria3.pdf
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26. Arbet-Engels C, Tartare-Deckert S, Eckhart W (February 1999). "C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor". The Journal of Biological Chemistry. 274 (9): 5422–8. doi:10.1074/jbc.274.9.5422. PMID 10026153.
27. Sehat B, Andersson S, Girnita L, Larsson O (July 2008). "Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis". Cancer Research. 68 (14): 5669–77. doi:10.1158/0008-5472.CAN-07-6364. PMID 18632619.
28. Rotem-Yehudar R, Galperin E, Horowitz M (August 2001). "Association of insulin-like growth factor 1 receptor with EHD1 and SNAP29". The Journal of Biological Chemistry. 276 (35): 33054–60. doi:10.1074/jbc.M009913200. PMID 11423532.
29. Vecchione A, Marchese A, Henry P, Rotin D, Morrione A (May 2003). "The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor". Molecular and Cellular Biology. 23 (9): 3363–72. doi:10.1128/mcb.23.9.3363-3372.2003. PMC 153198. PMID 12697834.
30. Dey BR, Frick K, Lopaczynski W, Nissley SP, Furlanetto RW (June 1996). "Evidence for the direct interaction of the insulin-like growth factor I receptor with IRS-1, Shc, and Grb10". Molecular Endocrinology. 10 (6): 631–41. doi:10.1210/mend.10.6.8776723. PMID 8776723.
31. He W, Rose DW, Olefsky JM, Gustafson TA (March 1998). "Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains". The Journal of Biological Chemistry. 273 (12): 6860–7. doi:10.1074/jbc.273.12.6860. PMID 9506989.
32. Morrione A, Valentinis B, Li S, Ooi JY, Margolis B, Baserga R (July 1996). "Grb10: A new substrate of the insulin-like growth factor I receptor". Cancer Research. 56 (14): 3165–7. PMID 8764099.
33. Mañes S, Mira E, Gómez-Mouton C, Zhao ZJ, Lacalle RA, Martínez-A C (April 1999). "Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility". Molecular and Cellular Biology. 19 (4): 3125–35. doi:10.1128/mcb.19.4.3125. PMC 84106. PMID 10082579.
34. Tartare-Deckert S, Sawka-Verhelle D, Murdaca J, Van Obberghen E (October 1995). "Evidence for a differential interaction of SHC and the insulin receptor substrate-1 (IRS-1) with the insulin-like growth factor-I (IGF-I) receptor in the yeast two-hybrid system". The Journal of Biological Chemistry. 270 (40): 23456–60. doi:10.1074/jbc.270.40.23456. PMID 7559507.
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36. Seely BL, Reichart DR, Staubs PA, Jhun BH, Hsu D, Maegawa H, Milarski KL, Saltiel AR, Olefsky JM (August 1995). "Localization of the insulin-like growth factor I receptor binding sites for the SH2 domain proteins p85, Syp, and GTPase activating protein". The Journal of Biological Chemistry. 270 (32): 19151–7. doi:10.1074/jbc.270.32.19151. PMID 7642582.
37. Santen RJ, Song RX, Zhang Z, Kumar R, Jeng MH, Masamura A, Lawrence J, Berstein L, Yue W (July 2005). "Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity". Endocrine-Related Cancer. 12. 12 Suppl 1: S61-73. doi:10.1677/erc.1.01018. PMID 16113100.
38. Dey BR, Spence SL, Nissley P, Furlanetto RW (September 1998). "Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-I receptor". The Journal of Biological Chemistry. 273 (37): 24095–101. doi:10.1074/jbc.273.37.24095. PMID 9727029.
39. Dey BR, Furlanetto RW, Nissley P (November 2000). "Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor". Biochemical and Biophysical Research Communications. 278 (1): 38–43. doi:10.1006/bbrc.2000.3762. PMID 11071852.
40. Craparo A, Freund R, Gustafson TA (April 1997). "14-3-3 (epsilon) interacts with the insulin-like growth factor I receptor and insulin receptor substrate I in a phosphoserine-dependent manner". The Journal of Biological Chemistry. 272 (17): 11663–9. doi:10.1074/jbc.272.17.11663. PMID 9111084.
41. Jiang L, Liu X, Chen Z, Jin Y, Heidbreder CE, Kolokythas A, Wang A, Dai Y, Zhou X (November 2010). "MicroRNA-7 targets IGF1R (insulin-like growth factor 1 receptor) in tongue squamous cell carcinoma cells". The Biochemical Journal. 432 (1): 199–205. doi:10.1042/BJ20100859. PMC 3130335. PMID 20819078.

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 Metastasis Reviews. 22 (4): 327–36. doi:10.1023/A:1023720928680. PMID 12884909.
• 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.
• 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. 243. pp. 215–85. doi:10.1016/S0074-7696(05)43004-1. ISBN 9780123646477. 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.

External links

• IGF-1+Receptor at the US 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.