Insulin-like growth factor (IGF)-I A- and B-domain analogues with altered type 1 IGF and insulin receptor binding specificities

1996 ◽  
Vol 17 (3) ◽  
pp. 237-246 ◽  
Author(s):  
G K Shooter ◽  
B Magee ◽  
M A Soos ◽  
G L Francis ◽  
K Siddle ◽  
...  
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Receptor Binding ◽  
Insulin Like Growth Factor ◽  
Receptor Isoforms ◽  
Insulin Receptor Isoforms ◽  
Igf I ◽  
Igf Receptor ◽  
Specificity Of Binding

ABSTRACT Insulin-like growth factor-I (IGF-I) analogues were produced with the aim of identifying IGF-I residues that contribute to the specificity of binding to the type 1 IGF receptor as opposed to the insulin receptor. Receptor binding properties of a series of A- and B-domain analogues were compared using rat L6 myoblasts, soluble human IGF type 1 receptors and soluble human insulin receptor isoforms HIR-A (−Ex11) and HIR-B (+Ex11). IGF-I analogues, [Leu8] IGF-I and [Phe59] IGF-I, were shown to exhibit respectively, a 28- and 17-fold decrease in affinity for the HIR-A with only a 6- and 5-fold decrease in affinity for the human IGF type 1 receptor. In contrast, the analogue [His4] IGF-I was equipotent to IGF-I in binding to the soluble type 1 IGF receptor while showing 7-fold and 4-fold increases in HIR-A and HIR-B binding respectively. Furthermore, [Leu62] IGF-I was 8-fold less potent than IGF-I in soluble IGF type 1 receptor binding but only showed a 2-fold decrease in HIR-A and HIR-B binding. Our study supports the conclusion that the co-evolution of the IGF-I and insulin receptor/ligand systems has resulted in subtle structural differences in the A- and B-regions of each ligand important for defining receptor binding specificity.

scholarly journals The C Region of Human Insulin-like Growth Factor (IGF) I Is Required for High Affinity Binding to the Type 1 IGF Receptor

1989 ◽  
Vol 264 (19) ◽  
pp. 11004-11008 ◽  
Author(s):  
M L Bayne ◽  
J Applebaum ◽  
D Underwood ◽  
G G Chicchi ◽  
B G Green ◽  
...  
Keyword(s):  
Growth Factor ◽  
Human Insulin ◽  
Affinity Binding ◽  
Insulin Like Growth Factor ◽  
High Affinity Binding ◽  
High Affinity ◽  
Igf I ◽  
Igf Receptor

scholarly journals Insulin-like growth factor (IGF) receptor, IGF-I, interleukin-1 beta (IL-1 beta), and IL-6 mRNA expression in osteoarthritic and normal human cartilage.

1996 ◽  
Vol 44 (2) ◽  
pp. 133-141 ◽  
Author(s):  
J Middleton ◽  
A Manthey ◽  
J Tyler
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Interleukin 1 ◽  
Insulin Like Growth Factor ◽  
Interleukin 1 Beta ◽  
Normal Cartilage ◽  
Igf I ◽  
Cartilage Cells ◽  
Igf Receptor

Insulin-like growth factor-I (IGF-I) stimulates the production of extracellular matrix by cartilage cells and this action is mediated through the Type 1 IGF receptor. Expression of the genes for the IGF receptor and for IGF-I was examined in normal and osteoarthritic (OA) human articular cartilage by in situ hybridization. RNA transcripts for Type 1 receptor were detected in all 73 tissue samples and in 80-100% of chondrocytes per section. Signal for the receptor was present in normal and OA cells, and the highest message levels were in the tissues exhibiting advanced pathology. Strong message signals in the cells of the more advanced lesions were also noted for IGF-I, whereas little or no IGF-I mRNA was detected in normal samples. Interleukin-1 beta (IL-1 beta) induces degradation of extracellular matrix by cartilage cells, and expression of this gene was examined with digoxygenin-labeled oligonucleotide probes. mRNA transcripts were detected in only one in five of the cartilage samples taken from OA joints. Unlike IGF-I, expression did not correlate with the degree of OA pathology and positive cells were demonstrated also in samples from young normal cartilage. IL-6 mRNA was present both in surface and deep cells of fibrillated OA cartilage, but no signal was evident in histologically normal cartilage from OA tissue or in normal young joints.

Characteristics of binding of insulin-like growth factor (IGF)-I and IGF-II analogues to the type 1 IGF receptor determined by BIAcore analysis

2002 ◽  
Vol 269 (3) ◽  
pp. 961-968 ◽  
Author(s):  
Briony E. Forbes ◽  
Perry J. Hartfield ◽  
Kerrie A. McNeil ◽  
Kathy H. Surinya ◽  
Steven J. Milner ◽  
...  
Keyword(s):  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Igf Receptor

scholarly journals Investigation of Insulin-Like Growth Factor (IGF)-I and Insulin Receptor Binding and Expression in Jejunum of Parenterally Fed Rats Treated with IGF-I or Growth Hormone1

Endocrinology ◽  
1999 ◽  
Vol 140 (10) ◽  
pp. 4850-4860 ◽  
Author(s):  
Denise M. Ney ◽  
David J. Huss ◽  
Melanie B. Gillingham ◽  
Karen R. Kritsch ◽  
Elizabeth M. Dahly ◽  
...  
Keyword(s):  
Growth Factor ◽  
Insulin Receptor ◽  
Receptor Binding ◽  
Insulin Like Growth Factor ◽  
Insulin Receptor Binding ◽  
Igf I

Transcriptional and post-translational regulation of insulin-like growth factor-binding protein-5 in rat articular chondrocytes

1996 ◽  
Vol 148 (2) ◽  
pp. 355-369 ◽  
Author(s):  
T Matsumoto ◽  
S E Gargosky ◽  
Y Oh ◽  
R G Rosenfeld
Keyword(s):  
Growth Factor ◽  
Articular Chondrocytes ◽  
Primary Cultures ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Factor Binding ◽  
Igf I ◽  
Igf Receptor ◽  
Dose Dependent

Abstract The aim of this study was to assess the regulation of insulin-like growth factor-binding proteins (IGFBPs) by IGFs in primary cultures of rat articular chondrocytes (RAC). Employing Western ligand blotting, immunoprecipitation and Northern blot analysis, RAC were found to secrete IGFBP-5 (29 kDa) and IGFBP-4 (24 kDa) as the predominant IGFBPs, as well as IGFBP-2 (32–30 kDa) and IGFBP-3 (43–39 kDa) as the minor species. Treatment of cells with IGF-I and IGF-II resulted in a dose-dependent increase of IGFBP-5 and a small increase in IGFBP-4 in conditioned media (CM). Des(1–3) IGF-I and [Gln6, Ala7,Tyr18, Leu19] IGF-II ([QAYL] IGF-II), which bind to the type 1 IGF receptor but not to IGFBPs, also induced IGFBP-5 peptide, although the increase was less than with IGF-I or IGF-II treatment of RAC. [Leu27] IGF-II, which does not bind to the type 1 IGF receptor but binds to IGFBPs, resulted in little induction of IGFBP-5, while [QAYL-Leu27] IGF-II, which has reduced affinity for both the type 1 IGF receptor and IGFBPs, did not increase IGFBP-5. These data suggest that the increase in IGFBP-5 in CM is modulated by both the type 1 IGF receptor and the interaction between IGFs and IGFBPs. Northern blotting analysis showed that IGF-I, IGF-II and des(1–3) IGF-I treatment of RAC increased steady state levels of IGFBP-5 mRNA, suggesting that the IGF-mediated increase in IGFBP-5 is transcriptionally modulated. Interestingly, the increase in IGFBP-5 peptide levels and mRNA were not parallel, suggesting the possibility of post-translational modifications of IGFBP-5, such as those seen with IGFBP-5 protease. IGFBP-5 protease activity was detectable in untreated CM, whereas treatment with IGF-I and IGF-II partially protected IGFBP-5 from proteolysis. In summary, treatment of RAC with IGF-I and IGF-II results in dose-dependent increases in both IGFBP-5 peptide in the CM and mRNA levels. These changes are mediated by interactions via the type 1 IGF receptor as well as IGFBPs, both transcriptionally and post-translationally. Journal of Endocrinology (1996) 148, 355–369

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