- Insulin-like growth factor 1 receptor
The Insulin-like Growth Factor 1 (IGF-1) Receptor is a transmembrane receptor that is activated by
IGF-1and by the related growth factor IGF-2. It belongs to the large class of tyrosine kinasereceptors. 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 muscleand other target tissues. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass, testifying to the strong growth-promoting effect of this receptor. Mice carrying only one functional copy of igf1r are normal, but exhibit a ~15% decrease in body mass.
tructure 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 Receptorand 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.
Tyrosine kinase receptors, including, the IGF-1 receptor, mediate their activity by causing the addition of a
phosphate groups to particular tyrosines on certain proteinswithin 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 muscleand 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
pregnancyand lactation. During pregnancy, there is intense proliferationof epithelial cellswhich form the duct and gland tissue. Following weaning, the cells undergo apoptosisand 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,cite journal | author = Warshamana-Greene GS, Litz J, Buchdunger E, García-Echeverría C, Hofmann F, Krystal GW | title = The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy | journal = Clin. Cancer Res. | volume = 11 | issue = 4 | pages = 1563–71 | year = 2005 | pmid = 15746061 | doi = 10.1158/1078-0432.CCR-04-1544 | issn = ] cite journal | author = Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI | title = Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells | journal = Endocr. Relat. Cancer | volume = 11 | issue = 4 | pages = 793–814 | year = 2004 | pmid = 15613453 | doi = 10.1677/erc.1.00799 | issn = ] most notably breast cancer. In some instances its anti-apoptotic properties allow cancerous cells to resist the
cytotoxicproperties of chemotheraputic drugs or radiotherapy. In others, where EGFR inhibitors such as erlotinibare 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 erlotinibpage), 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 AG538cite journal | author = Blum G, Gazit A, Levitzki A | title = Substrate competitive inhibitors of IGF-1 receptor kinase | journal = Biochemistry | volume = 39 | issue = 51 | pages = 15705–12 | year = 2000 | pmid = 11123895 | doi = | issn = ] 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 IGF-1R over IR.
Monoclonal antibodiesare 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.cite journal | author = Saeed O, Yaghmaie F, Garan SA, Gouw AM, Voelker MA, Sternberg H, Timiras PS | title = Insulin-like growth factor-1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice | journal = Int. J. Dev. Neurosci. | volume = 25 | issue = 1 | pages = 23–8 | year = 2007 | pmid = 17194562 | doi = 10.1016/j.ijdevneu.2006.11.004 | issn = ] cite journal | author = Yaghmaie F, Saeed O, Garan SA, Voelker MA, Gouw AM, Freitag W, Sternberg H, Timiras PS | title = Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice | journal = Int. J. Dev. Neurosci. | volume = 24 | issue = 7 | pages = 431–6 | year = 2006 | pmid = 17034982 | doi = 10.1016/j.ijdevneu.2006.08.008 | issn = ] [cite journal |author=F. Yaghmaie, O. Saeed, S.A. Garan, A.M. Gouw, P. Jafar, J. Kaur, S. Nijjar, P.S. Timiras, H. Sternberg, M.A. Voelker |title=Tracking changes in hypothalamic IGF-1 sensitivity with aging and caloric restriction |journal=Experimental Gerontology |volume=42 |issue=1-2 |pages=148–149 |year=2007 | doi = 10.1016/j.exger.2006.06.043 ] .
On the other hand, mice genetically engeneered to express only one functional copy have been reported to have an extension in average and maximal lifespan, of up to 33%.
*cite journal | author=Benito M, Valverde AM, Lorenzo M |title=IGF-I: a mitogen also involved in differentiation processes in mammalian cells. |journal=Int. J. Biochem. Cell Biol. |volume=28 |issue= 5 |pages= 499–510 |year= 1996 |pmid= 8697095 |doi=
*cite journal | author=Butler AA, Yakar S, Gewolb IH, "et al." |title=Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology. |journal=Comp. Biochem. Physiol. B, Biochem. Mol. Biol. |volume=121 |issue= 1 |pages= 19–26 |year= 1999 |pmid= 9972281 |doi=
*cite journal | author=Zhang X, Yee D |title=Tyrosine kinase signalling in breast cancer: insulin-like growth factors and their receptors in breast cancer. |journal=Breast Cancer Res. |volume=2 |issue= 3 |pages= 170–5 |year= 2001 |pmid= 11250706 |doi=
*cite journal | author=Gross JM, Yee D |title=The type-1 insulin-like growth factor receptor tyrosine kinase and breast cancer: biology and therapeutic relevance. |journal=Cancer Metastasis Rev. |volume=22 |issue= 4 |pages= 327–36 |year= 2004 |pmid= 12884909 |doi=
*cite journal | author=Adams TE, McKern NM, Ward CW |title=Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor. |journal=Growth Factors |volume=22 |issue= 2 |pages= 89–95 |year= 2005 |pmid= 15253384 |doi=
*cite journal | author=Surmacz E, Bartucci M |title=Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer. |journal=J. Exp. Clin. Cancer Res. |volume=23 |issue= 3 |pages= 385–94 |year= 2005 |pmid= 15595626 |doi=
*cite journal | author=Wood AW, Duan C, Bern HA |title=Insulin-like growth factor signaling in fish. |journal=Int. Rev. Cytol. |volume=243 |issue= |pages= 215–85 |year= 2005 |pmid= 15797461 |doi= 10.1016/S0074-7696(05)43004-1
*cite journal | author=Sarfstein R, Maor S, Reizner N, "et al." |title=Transcriptional regulation of the insulin-like growth factor-I receptor gene in breast cancer. |journal=Mol. Cell. Endocrinol. |volume=252 |issue= 1-2 |pages= 241–6 |year= 2006 |pmid= 16647191 |doi= 10.1016/j.mce.2006.03.018
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