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Insulin-like growth factor 1 receptor




Insulin-like growth factor 1 receptor
PDB rendering based on 1igr.
Available structures: 1igr, 1jqh, 1k3a, 1m7n, 1p4o, 2oj9
Identifiers
Symbol(s) IGF1R; CD221; IGFIR; JTK13; MGC142170; MGC142172; MGC18216
External IDs OMIM: 147370 MGI: 96433 Homologene: 30997
RNA expression pattern

More reference expression data

Orthologs
Human Mouse
Entrez 3480 16001
Ensembl ENSG00000140443 ENSMUSG00000005533
Uniprot P08069 Q3U1L4
Refseq NM_000875 (mRNA)
NP_000866 (protein)
NM_010513 (mRNA)
NP_034643 (protein)
Location Chr 15: 97.01 - 97.32 Mb Chr 7: 67.83 - 68.1 Mb
Pubmed search [2] [3]

The Insulin-like Growth Factor 1 (IGF-1) Receptor is a transmembrane receptor that is activated by IGF-1 and by the related growth factor 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.

Additional recommended knowledge

Contents

Structure of receptor

Two alpha subunits and two beta subunits make up the IGF-1 receptor. The beta subunits pass through the cellular membrane and are linked by disulfide bonds. 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 IR both have a binding site for ATP, which is used to provide the phoshates for autophosphorylation (see below). There is a 60% homology between IGF-1R and the insulin receptor.

Receptor family

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.

The IGF-1R is implicated in several cancers,[1][2] most notably breast cancer. In some instances its anti-apoptotic properties allow cancerous cells to resist the cytotoxic properties of chemotheraputic drugs or radiotherapy. In others, where EGFR inhibitors such as erlotinib are being used to inhibit the EGFR signalling 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 signalling 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 inferring the ability to promote vascularisation.

IGF-1 vs Insulin Receptor 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 the insulin receptor. 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-InsulinReceptor 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).

Inhibitors of IGF-1R

Due to the similarity of the structures of IGF-1R and the insulin receptor, 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[3] 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, which show far greater (100 fold) selectivity towards IFG-1R over IR.
  • 3) Monoclonal antibodies are probably the most specific and promising therapeutic compounds.

Effects of aging on IGF-1R

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. [4] [5] [6]

References

  1. ^ Warshamana-Greene G, Litz J, Buchdunger E, García-Echeverría C, Hofmann F, Krystal G (2005). "The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy". Clin Cancer Res 11 (4): 1563-71. PMID 15746061.
  2. ^ Jones H et al (2004). "Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells". Endocr Relat Cancer 11 (4): 793-814. PMID 15613453.
  3. ^ Blum G, Gazit A, Levitzki A (2000). "Substrate competitive inhibitors of IGF-1 receptor kinase". Biochemistry 39 (51): 15705-12. PMID 11123895.
  4. ^ Saeed O,Yaghmaie F,Garan SA,Gouw AM,Voelker MA,Sternberg H, Timiras PS. (2007). "Insulin-like growth factor-1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice". Int J Dev Neurosci 25 (1): 23-8. PMID 17194562.
  5. ^ Yaghmaie F, Saeed O, Garan SA, Voelker MA, Gouw AM, Freitag W, Sternberg H, Timiras PS (2006). "Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice". Int J Dev Neurosci 24 (7): 431-6. PMID 17034982.
  6. ^ F. Yaghmaie, O. Saeed, S.A. Garan, A.M. Gouw, P. Jafar, J. Kaur, S. Nijjar, P.S. Timiras, H. Sternberg, M.A. Voelker (2007). "Tracking changes in hypothalamic IGF-1 sensitivity with aging and caloric restriction". Experimental Gerontology 42 (1-2): 148-149. [1]

See also

Further reading

  • Benito M, Valverde AM, Lorenzo M (1996). "IGF-I: a mitogen also involved in differentiation processes in mammalian cells.". Int. J. Biochem. Cell Biol. 28 (5): 499-510. PMID 8697095.
  • Butler AA, Yakar S, Gewolb IH, et al. (1999). "Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology.". Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 121 (1): 19-26. 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 Res. 2 (3): 170-5. PMID 11250706.
  • Gross JM, Yee D (2004). "The type-1 insulin-like growth factor receptor tyrosine kinase and breast cancer: biology and therapeutic relevance.". Cancer Metastasis Rev. 22 (4): 327-36. PMID 12884909.
  • Adams TE, McKern NM, Ward CW (2005). "Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor.". Growth Factors 22 (2): 89-95. PMID 15253384.
  • Surmacz E, Bartucci M (2005). "Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer.". J. Exp. Clin. Cancer Res. 23 (3): 385-94. PMID 15595626.
  • Wood AW, Duan C, Bern HA (2005). "Insulin-like growth factor signaling in fish.". Int. Rev. Cytol. 243: 215-85. doi:10.1016/S0074-7696(05)43004-1. PMID 15797461.
  • Sarfstein R, Maor S, Reizner N, et al. (2006). "Transcriptional regulation of the insulin-like growth factor-I receptor gene in breast cancer.". Mol. Cell. Endocrinol. 252 (1-2): 241-6. doi:10.1016/j.mce.2006.03.018. PMID 16647191.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Insulin-like_growth_factor_1_receptor". A list of authors is available in Wikipedia.
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