Insulin-like growth factor 1 receptor
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| Location (UCSC) | Chr 15: 98.65 – 98.96 Mb | Chr 7: 67.6 – 67.88 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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The insulin-like growth factor 1 (IGF-1) receptor is a
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.[5] 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.[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]
Family members
Tyrosine kinase receptors, including the IGF-1 receptor, mediate their activity by causing the addition of a
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
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.[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-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.[10][11]
Craniosynostosis
Mutations in IGF1R have been associated with craniosynostosis.[12]
Body size
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]
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.[14]
Clinical significance
Cancer
The IGF-1R is implicated in several cancers,
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 using glucocorticoids were induced into a reversible dormancy state which was dependent on the IGF-1R and its accompanying survival signaling pathways.[23]
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:
- 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]
- 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
Regulation
There is evidence to suggest that IGF1R is negatively regulated by the microRNA miR-7.[42]
See also
- Hypothalamic–pituitary–somatic axis
- Insulin receptor
- Linsitinib, an inhibitor of IGF-1R in clinical trials for cancer treatment
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000140443 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005533 – Ensembl, May 2017
- ^ "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.
- ISBN 81-7895-002-2.
- PMID 26628682.
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- PMID 7540132.
- PMID 24189571.
- S2CID 5828689.
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- ^ PMID 22903739.
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- ^ "Archived copy" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2012-07-18.
{{cite web}}: CS1 maint: archived copy as title (link) - PMID 11724822.
- PMID 10026153.
- ^ PMID 18632619.
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Further reading
- Benito M, Valverde AM, Lorenzo M (May 1996). "IGF-I: a mitogen also involved in differentiation processes in mammalian cells". The International Journal of Biochemistry & Cell Biology. 28 (5): 499–510. PMID 8697095.
- Butler AA, Yakar S, Gewolb IH, Karas M, Okubo Y, LeRoith D (September 1998). "Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology". Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. 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 Research. 2 (3): 170–5. PMID 11250706.
- Gross JM, Yee D (December 2003). "The type-1 insulin-like growth factor receptor tyrosine kinase and breast cancer: biology and therapeutic relevance". Cancer and Metastasis Reviews. 22 (4): 327–36. S2CID 35963688.
- Adams TE, McKern NM, Ward CW (June 2004). "Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor". Growth Factors. 22 (2): 89–95. S2CID 86844427.
- Surmacz E, Bartucci M (September 2004). "Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer". Journal of Experimental & Clinical Cancer Research. 23 (3): 385–94. PMID 15595626.
- Wood AW, Duan C, Bern HA (2005). Insulin-like growth factor signaling in fish. International Review of Cytology. Vol. 243. pp. 215–85. PMID 15797461.
- Sarfstein R, Maor S, Reizner N, Abramovitch S, Werner H (June 2006). "Transcriptional regulation of the insulin-like growth factor-I receptor gene in breast cancer". Molecular and Cellular Endocrinology. 252 (1–2): 241–6. S2CID 24895685.
External links
- IGF-1+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P08069 (Insulin-like growth factor 1 receptor) at the PDBe-KB.
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