Precise mapping of an IGF-I-binding site on the IGF-1R

Keyhanfar, Mehrnaz; Booker, Grant W.; Whittaker, Jonathan; Wallace, John C.; Forbes, Briony E.

doi:10.1042/bj20060890

Cited by 44 publications

(39 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The higher affinity binding site "A" is exactly the same as the interaction for the C-domain of IGF. This site of interaction occurs with the cysteine-rich domain of IGF-1R at the cluster of residues Phe 241 , Phe 251 , and Phe 266 , which has been demonstrated using monoclonal antibodies and site-directed mutagenesis (30). This information provides insights into the future design of IGF-1R agonists for drug discovery.…”

Section: Discussionmentioning

confidence: 99%

Specific Activation of Insulin-like Growth Factor-1 Receptor by Ginsenoside Rg5 Promotes Angiogenesis and Vasorelaxation

Cho

Hur

Kim

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The mechanism by which ginsenoside Rg5 regulates vascular function remains unclear. Results: Rg5 increases angiogenesis and vasorelxation by activating multiple signal transduction pathways downstream of insulin-like growth fastor-1 receptor (IGF-1R). Conclusion: Rg5 promotes endothelial cell function through activation of IGF-1R. Significance: These findings reveal a mechanism for the positive regulation of vascular function by Rg5-mediated IGF-1R activation.

show abstract

Section: Discussionmentioning

confidence: 99%

Specific Activation of Insulin-like Growth Factor-1 Receptor by Ginsenoside Rg5 Promotes Angiogenesis and Vasorelaxation

Cho

Hur

Kim

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In addition, these two mAbs also inhibit IGF-II binding to both wtIGF-1R and sIGF1Rs but to a lesser extent than that seen with IGF-I, suggesting that the ligand binding sites for IGF-I and IGF-II in that domain may be slightly different. The epitope of the inhibitory 24-60 mAb located within the CR of the IGF-1R (45) is similar to that of ␣IR3 and has recently been shown to overlap with residues important for IGF-I but not IGF-II binding (52). The mAb 24-60 affects the binding of IGF-I to both membrane-associated and solubilized receptors, with a more pronounced effect on membrane-associated receptors (45).…”

Section: Discussionmentioning

confidence: 99%

An Investigation of the Ligand Binding Properties and Negative Cooperativity of Soluble Insulin-like Growth Factor Receptors

Surinya

Forbes

Occhiodoro

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

To investigate the interaction of the insulin-like growth factor (IGF) ligands with the insulin-like growth factor type 1 receptor (IGF-1R), we have generated two soluble variants of the IGF-1R. We have recombinantly expressed the ectodomain of IGF-1R or fused this domain to the constant domain from the Fc fragment of mouse immunoglobulin. The ligand binding properties of these soluble IGF-1Rs for IGF-I and IGF-II were investigated using conventional ligand competition assays and BIAcore biosensor technology. In ligand competition assays, the soluble IGF-1Rs both bound IGF-I with similar affinities and a 5-fold lower affinity than that seen for the wild type receptor. In addition, both soluble receptors bound IGF-II with similar affinities to the wild type receptor. BIAcore analyses showed that both soluble IGF-1Rs exhibited similar ligand-specific association and dissociation rates for IGF-I and for IGF-II. The soluble IGF-1R proteins both exhibited negative cooperativity for IGF-I, IGF-II, and the 24-60 antibody, which binds to the IGF-1R cysteine-rich domain. We conclude that the addition of the selfassociating Fc domain to the IGF-1R ectodomain does not affect ligand binding affinity, which is in contrast to the soluble ectodomain of the IR. This study highlights some significant differences in ligand binding modes between the IGF-1R and the insulin receptor, which may ultimately contribute to the different biological activities conferred by the two receptors. Despite their similarity in sequence and structure IGF-I and IGF-II can stimulate both overlapping and distinct biological functions (reviewed in Ref. 9). This is evident in patients with IGF-I deficiency, which results in severe growth and mental retardation, where IGF-II does not compensate for the loss of IGF-I activity (10 -12). Therefore, in order to understand how both IGF-I and IGF-II stimulate their respective biological outcomes, we first need to understand the mechanism by which both ligands bind and in turn activate the IGF-1R. Insulin-like growth factors (IGFsThe IGF-1R is a member of the tyrosine kinase family of receptors and, together with the insulin receptor (IR) and insulin-related receptor, forms a subfamily with similar structural organization (reviewed in Ref. 9). The IGF-1R and IR are homodimers composed of two ␣ and two ␤ subunits and are synthesized as a single precursor polypeptide, which is then post-translationally processed by dimerization, proteolytic cleavage, and glycosylation.The amino-terminal regions of the ␣ chain of these receptors are composed of three domains, two structurally homologous subdomains designated large homologous domain 1 (L1) and large homologous domain 2 (L2), which are separated by a cysteine-rich (CR) domain of ϳ160 amino acids (3) (see supplemental Fig. S1). The major ligand binding determinants of the structurally related IGF-1R and IR reside within the extracellular ␣ subunits of the receptors (reviewed in Refs. 9, 13, and 14). Studies performed with truncated IRs have demonstrated that dimeriza...

show abstract

“…Most evident is IGFBP6, which was neither found in any archosaurs (birds and crocodilians) nor in platypus (8). The 5′ end of IGFBP6 was truncated in nearly all other reptiles including genome-derived ENSEMBL sequences of the Anolis lizard and the Pelodiscus (36). Labeled sites (IGF1 S37 and N251; human numbering) are known to affect IGF hormone and receptor binding (Table S4).…”

Section: Binding Proteins Exhibit Putative Truncations Of Important Fmentioning

confidence: 99%

“…In reptiles, positively selected sites were clustered on the hormone-binding surface of the IGF1R CR domain and in the binding pocket of INSR. They include IGF1R site F251, which affects IGF1-IGF1R binding in humans through its interaction with the IGF1 C-domain (36) (Table S4).…”

Section: Positive Selection In the Iis/tor Hormones And Receptors Showmentioning

confidence: 99%

“…IGF hormones bind to the receptors IGF1R and INSR by interacting with specific domains on each receptor (L1, CR, and L2) (36,37). Variation in the C-domain of IGF1 and IGF2 can regulate binding specificity to IGF1R (38) and to INSR (39) through the interactions of the C-domain of the hormones with the CR-domain in the binding pocket of IGF1R and INSR (36) (Fig.…”

Section: Positive Selection In the Iis/tor Hormones And Receptors Showmentioning

confidence: 99%

See 1 more Smart Citation

Rapid molecular evolution across amniotes of the IIS/TOR network

McGaugh

Bronikowski

Kuo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The insulin/insulin-like signaling and target of rapamycin (IIS/TOR) network regulates lifespan and reproduction, as well as metabolic diseases, cancer, and aging. Despite its vital role in health, comparative analyses of IIS/TOR have been limited to invertebrates and mammals. We conducted an extensive evolutionary analysis of the IIS/TOR network across 66 amniotes with 18 newly generated transcriptomes from nonavian reptiles and additional available genomes/transcriptomes. We uncovered rapid and extensive molecular evolution between reptiles (including birds) and mammals: (i) the IIS/TOR network, including the critical nodes insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K), exhibit divergent evolutionary rates between reptiles and mammals; (ii) compared with a proxy for the rest of the genome, genes of the IIS/TOR extracellular network exhibit exceptionally fast evolutionary rates; and (iii) signatures of positive selection and coevolution of the extracellular network suggest reptile-and mammal-specific interactions between members of the network. In reptiles, positively selected sites cluster on the binding surfaces of insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and insulin receptor (INSR); whereas in mammals, positively selected sites clustered on the IGF2 binding surface, suggesting that these hormone-receptor binding affinities are targets of positive selection. Further, contrary to reports that IGF2R binds IGF2 only in marsupial and placental mammals, we found positively selected sites clustered on the hormone binding surface of reptile IGF2R that suggest that IGF2R binds to IGF hormones in diverse taxa and may have evolved in reptiles. These data suggest that key IIS/TOR paralogs have sub-or neofunctionalized between mammals and reptiles and that this network may underlie fundamental life history and physiological differences between these amniote sister clades.insulin signaling | insulin growth factor | molecular evolution | rapamycin T he last 20 y has provided overwhelming support that the insulin-and insulin-like signaling/target of rapamycin (IIS/TOR) molecular network responds to stress and nutrients and underlies a wide range of physiological functions (1); cancer, metabolic syndrome, and diabetes (2); and the timing of life events (e.g., growth, maturation, reproduction, and aging) (3). The vertebrate IIS/TOR network consists of peptide hormones, binding proteins that regulate hormone bioavailability, and cell membrane receptors (hereafter, extracellular proteins of the IIS/TOR network) that induce an intracellular signaling cascade (hereafter, intracellular proteins of the IIS/TOR network) to stimulate cell proliferation, survival, and metabolism (Fig. S1). The core intracellular signal transduction genes in this network are largely conserved across deep phylogenetic time (4, 5). In contrast, genes encoding the IIS/TOR extracellular network have diverged in the vertebrate lineage (6-8) and may have variable roles among taxa (9, 10). Despite its central rol...

show abstract

Precise mapping of an IGF-I-binding site on the IGF-1R

Cited by 44 publications

References 45 publications

Specific Activation of Insulin-like Growth Factor-1 Receptor by Ginsenoside Rg5 Promotes Angiogenesis and Vasorelaxation

Specific Activation of Insulin-like Growth Factor-1 Receptor by Ginsenoside Rg5 Promotes Angiogenesis and Vasorelaxation

An Investigation of the Ligand Binding Properties and Negative Cooperativity of Soluble Insulin-like Growth Factor Receptors

Rapid molecular evolution across amniotes of the IIS/TOR network

Contact Info

Product

Resources

About