Insulin-like growth factor 1 receptor explained

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.

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.[1] 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.[2]

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.[3] [4]

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.[5] 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.[6] [7]

Craniosynostosis

Mutations in IGF1R have been associated with craniosynostosis.[8]

Body size

IGF-1R has been shown to have a significant effect on body size in small dog breeds. 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.[9]

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.[10]

Clinical significance

Cancer

The IGF-1R is implicated in several cancers,[11] [12] 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.[13] Evidence suggests that IGF-IR signaling is required for survival and growth when prostate cancer cells progress to androgen independence.[14] In addition, when immortalized prostate cancer cells mimicking advanced disease are treated with the IGF-1R ligand, IGF-1, the cells become more motile.[15] Members of the IGF receptor family and their ligands also seem to be involved in the carcinogenesis of mammary tumors of dogs.[16] [17] 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.[18]

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.[19]

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[20] 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.[21]
  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:

Regulation

There is evidence to suggest that IGF1R is negatively regulated by the microRNA miR-7.[38]

See also

Further reading

Notes and References

  1. Gregory CW, DeGeorges A, Sikes RA . The IGF axis in the development and progression of prostate cancer . Recent Research Developments in Cancer . 437–462 . 2001 . 81-7895-002-2.
  2. Xu Q, Malecka KL, Fink L, Jordan EJ, Duffy E, Kolander S, Peterson JR, Dunbrack RL . Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases . Science Signaling . 8 . 405 . rs13 . December 2015 . 26628682 . 4766099 . 10.1126/scisignal.aaa6711 .
  3. Jones JI, Clemmons DR . Insulin-like growth factors and their binding proteins: biological actions . Endocrine Reviews . 16 . 1 . 3–34 . February 1995 . 7758431 . 10.1210/edrv-16-1-3 .
  4. LeRoith D, Werner H, Beitner-Johnson D, Roberts CT . Molecular and cellular aspects of the insulin-like growth factor I receptor . Endocrine Reviews . 16 . 2 . 143–63 . April 1995 . 7540132 . 10.1210/edrv-16-2-143 .
  5. 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. 10.1016/j.bbcan.2013.10.005. 24189571.
  6. Saeed O, Yaghmaie F, Garan SA, Gouw AM, Voelker MA, Sternberg H, Timiras PS . 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 . February 2007 . 17194562 . 10.1016/j.ijdevneu.2006.11.004 . 5828689 . free .
  7. Yaghmaie F, Saeed O, Garan SA, Voelker MA, Gouw AM, Freitag W, Sternberg H, Timiras PS . 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 . November 2006 . 17034982 . 10.1016/j.ijdevneu.2006.08.008 . 22533403 .
  8. Cunningham ML, Horst JA, Rieder MJ, Hing AV, Stanaway IB, Park SS, Samudrala R, Speltz ML . IGF1R variants associated with isolated single suture craniosynostosis . American Journal of Medical Genetics. Part A . 155A . 1 . 91–7 . January 2011 . 21204214 . 3059230 . 10.1002/ajmg.a.33781 .
  9. Hoopes BC, Rimbault M, Liebers D, Ostrander EA, Sutter NB . The insulin-like growth factor 1 receptor (IGF1R) contributes to reduced size in dogs . Mammalian Genome . 23 . 11–12 . 780–90 . December 2012 . 22903739 . 3511640 . 10.1007/s00335-012-9417-z .
  10. Book: Harris JR, Lippman ME, Osborne CK, Morrow M . Diseases of the Breast. 28 March 2012. Lippincott Williams & Wilkins . 978-1-4511-4870-1 . 88–.
  11. Warshamana-Greene GS, Litz J, Buchdunger E, García-Echeverría C, Hofmann F, Krystal GW . 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 . February 2005 . 15746061 . 10.1158/1078-0432.CCR-04-1544 . 12090402 .
  12. Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI . 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 . December 2004 . 15613453 . 10.1677/erc.1.00799 . 11392/523178 . 19466790 . free .
  13. Hellawell GO, Turner GD, Davies DR, Poulsom R, Brewster SF, Macaulay VM . 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 . May 2002 . 12019176 .
  14. Krueckl SL, Sikes RA, Edlund NM, Bell RH, Hurtado-Coll A, Fazli L, Gleave ME, Cox ME . Increased insulin-like growth factor I receptor expression and signaling are components of androgen-independent progression in a lineage-derived prostate cancer progression model . Cancer Research . 64 . 23 . 8620–9 . December 2004 . 15574769 . 10.1158/0008-5472.CAN-04-2446 . free .
  15. Yao H, Dashner EJ, van Golen CM, van Golen KL . RhoC GTPase is required for PC-3 prostate cancer cell invasion but not motility . Oncogene . 25 . 16 . 2285–96 . April 2006 . 16314838 . 10.1038/sj.onc.1209260 . free .
  16. Klopfleisch R, Hvid H, Klose P, da Costa A, Gruber AD . 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 . December 2010 . 21062411 . 10.1111/j.1476-5829.2009.00232.x .
  17. Klopfleisch R, Lenze D, Hummel M, Gruber AD . Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles . BMC Cancer . 10 . 618 . November 2010 . 21062462 . 2994823 . 10.1186/1471-2407-10-618 . free .
  18. Chen Y, McGee J, Chen X, Doman TN, Gong X, Zhang Y, Hamm N, Ma X, Higgs RE, Bhagwat SV, Buchanan S, Peng SB, Staschke KA, Yadav V, Yue Y, Kouros-Mehr H . Identification of druggable cancer driver genes amplified across TCGA datasets . PLOS ONE . 9 . 5 . e98293 . 2014 . 24874471 . 4038530 . 10.1371/journal.pone.0098293 . 2014PLoSO...998293C . free .
  19. Prekovic S, Schuurman K, Mayayo-Peralta I, Manjón AG, Buijs M, Yavuz S, Wellenstein MD, Barrera A, Monkhorst K, Huber A, Morris B. Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer. Nature Communications. 12. 1. July 2021. 4360. 10.1038/s41467-021-24537-3. 34272384. 8285479. 2021NatCo..12.4360P. free .
  20. Blum G, Gazit A, Levitzki A . Substrate competitive inhibitors of IGF-1 receptor kinase . Biochemistry . 39 . 51 . 15705–12 . December 2000 . 11123895 . 10.1021/bi001516y .
  21. Web site: Archived copy . 2012-07-18 . 2016-03-04 . https://web.archive.org/web/20160304090810/http://www.targeting-the-kinome.org/images/Garcia-Echeverria3.pdf . dead .
  22. Taya S, Inagaki N, Sengiku H, Makino H, Iwamatsu A, Urakawa I, Nagao K, Kataoka S, Kaibuchi K . Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF . The Journal of Cell Biology . 155 . 5 . 809–20 . November 2001 . 11724822 . 2150867 . 10.1083/jcb.200106139 .
  23. Arbet-Engels C, Tartare-Deckert S, Eckhart W . C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor . The Journal of Biological Chemistry . 274 . 9 . 5422–8 . February 1999 . 10026153 . 10.1074/jbc.274.9.5422 . free .
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