Insulin-like growth factor 1 receptor 5503004 224271133 2008-07-08T02:32:04Z ProteinBoxBot 3991663 Replaced protein Box Template with PBB Template for easy viewing. {{PBB|geneid=3480}} The '''Insulin-like Growth Factor 1 (IGF-1) Receptor''' is a [[transmembrane receptor|transmembrane]] [[receptor (proteomics)|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. 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. ==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 bond]]s. The receptor is a member of a family which consists of the [[Insulin Receptor]] and the [[Insulin-like growth factor 2 receptor|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 [[adenosine triphosphate|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 group]]s 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,<ref name="pmid15746061">{{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 = }}</ref><ref name="pmid15613453">{{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 = }}</ref> 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 [[Epidermal growth factor receptor|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<ref name="pmid11123895">{{cite 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 = }}</ref> 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. * 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 [[calorie restriction|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.<ref name="pmid17194562">{{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 = }}</ref><ref name="pmid17034982">{{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 = }}</ref><ref>{{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 }}</ref>. 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%. == References == {{reflist|2}} == See also == * [[Insulin receptor]] ==Further reading== {{refbegin | 2}} {{PBB_Further_reading | citations = *{{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 }} }} {{refend}} == External links == * {{MeshName|IGF-1+Receptor}} {{Clusters of differentiation}} {{Growth factor receptors}} {{Receptor tyrosine kinases}} [[Category:Clusters of differentiation]] [[Category:Tyrosine kinase receptors]] [[Category:Integral membrane proteins]] <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = no | update_citations = yes }}