Theinsulin-like growth factor 1 (IGF-1)receptor is aprotein found on the surface of humancells. It is atransmembranereceptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone calledIGF-2. It belongs to the large class oftyrosine 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 ofskeletal 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.
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 intracellularsignal 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 theinsulin receptor and theIGF-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 forATP, which is used to provide the phosphates forautophosphorylation. 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]
Tyrosine kinase receptors, including the IGF-1 receptor, mediate their activity by causing the addition of aphosphate groups to particular tyrosines on certainproteins 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 asskeletal muscle andcardiac muscle.
The IGFR signalling pathway is of critical importance during normal development of mammary gland tissue duringpregnancy andlactation. During pregnancy, there is intenseproliferation ofepithelial cells which form the duct and gland tissue. Following weaning, the cells undergoapoptosis 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.
IGF-1 binds to at least two cell surface receptors: the IGF1 Receptor (IGFR), and theinsulin 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-1in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia).
Studies in female mice have shown that bothsupraoptic nucleus (SON) andparaventricular nucleus (PVN) lose approximately one-third of IGF-1R immunoreactive cells with normal aging. Also, oldcalorically 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]
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]
Deletion of the IGF-1 receptor gene in mice results in lethality during earlyembryonic development, and for this reason, IGF-1 insensitivity, unlike the case ofgrowth hormone (GH) insensitivity (Laron syndrome), is not observed in the human population.[14]
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 thecytotoxic properties of chemotherapeutic drugs or radiotherapy. In breast cancer, whereEGFR inhibitors such aserlotinib 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 theerlotinib 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 usingglucocorticoids were induced into a reversible dormancy state which was dependent on the IGF-1R and its accompanying survival signaling pathways.[23]
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:
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.
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]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Gregory CW, DeGeorges A, Sikes RA (2001). "The IGF axis in the development and progression of prostate cancer".Recent Research Developments in Cancer:437–462.ISBN81-7895-002-2.
^Jones JI, Clemmons DR (February 1995). "Insulin-like growth factors and their binding proteins: biological actions".Endocrine Reviews.16 (1):3–34.doi:10.1210/edrv-16-1-3.PMID7758431.
^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.PMID7540132.
^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.PMID17034982.S2CID22533403.
^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.PMID15746061.S2CID12090402.
^Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM (May 2002). "Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease".Cancer Research.62 (10):2942–50.PMID12019176.
^Klopfleisch R, Hvid H, Klose P, da Costa A, Gruber AD (December 2010). "Insulin receptor is expressed in normal canine mammary gland and benign adenomas but decreased in metastatic canine mammary carcinomas similar to human breast cancer".Veterinary and Comparative Oncology.8 (4):293–301.doi:10.1111/j.1476-5829.2009.00232.x.PMID21062411.
^abcSehat 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.PMID18632619.
^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.PMID8764099.
^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.PMID16113100.S2CID18995886.
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