scholarly journals A key functional role for the insulin-like growth factor 1 N-terminal pentapeptide

1989 ◽  
Vol 259 (3) ◽  
pp. 665-671 ◽  
Author(s):  
C J Bagley ◽  
B L May ◽  
L Szabo ◽  
P J McNamara ◽  
M Ross ◽  
...  
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Biological Properties ◽  
Maximal Response ◽  
Insulin Like Growth Factor ◽  
Amino Acid Residues ◽  
Binding Studies ◽  
N Terminus ◽  
L6 Myoblast

In order to elucidate the role of the N-terminus of insulin-like growth factor 1 (IGF-1) with respect to its biological properties, we chemically synthesized analogues of IGF-1 truncated by one to five amino acid residues from the N-terminus. In a bioassay that measured the stimulation of protein synthesis in rat L6 myoblasts, the concentrations required to produce a half-maximal response were: IGF-1, 13 ng/ml; des-(1)-IGF-1, 10 ng/ml; des-(1-2)-IGF-1, 13 ng/ml; des-(1-3)-IGF-1, 1.5 ng/ml; des-(1-4)-IGF-1, 5.1 ng/ml; des-(1-5)-IGF-1, 1200 ng/ml. When tested for their abilities to compete with 125I-IGF-1 binding to L6 myoblasts at 3 degrees C, the concentrations required for 50% competition were: IGF-1, des-(1)-IGF-1 and des-(1-2)-IGF-1, 20 ng/ml; des-(1-3)-IGF-1, 14 ng/ml; des-(1-4)-IGF-1, 40 ng/ml; des-(1-5)-IGF-1, greater than 1000 ng/ml. Receptor-binding experiments at 25 degrees C, however, gave results suggesting that the myoblasts were secreting a binding protein selective for the three longest peptides. This interpretation was confirmed by binding studies with medium conditioned by the L6 myoblasts as well as binding protein purified from MDBK-cell-conditioned medium. In both cases IGF-1, des-(1)-IGF-1 and des-(1-2)-IGF-1 competed for tracer IGF-1 binding at least 60-fold better than did the three shorter peptides. The results obtained account for the increased potency of des-(1-3)-IGF-1 and des-(1-4)-IGF-1, since their activities are not attenuated by the binding protein, and the relatively lower potency of des-(1-4)-IGF-1 is a consequence of this peptide binding less well to the L6-myoblast receptor.

scholarly journals Emerging role of insulin-like growth factor-binding protein 7 in hepatocellular carcinoma

2014 ◽  
pp. 9
Author(s):  
Devanand Sarkar ◽  
Maaged Akiel ◽  
Devaraja Rajasekaran ◽  
Rachel Gredler ◽  
Ayesha Siddiq ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Factor Binding

scholarly journals Mutations in the B-domain of insulin-like growth factor-I influence the oxidative folding to yield products with modified biological properties

1995 ◽  
Vol 308 (3) ◽  
pp. 865-871 ◽  
Author(s):  
S J Milner ◽  
G L Francis ◽  
J C Wallace ◽  
B A Magee ◽  
F J Ballard
Keyword(s):  
Growth Factor ◽  
Biological Properties ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Oxidative Folding ◽  
Biological Assays ◽  
Igf I ◽  
Igf Binding ◽  
L6 Myoblast

The oxidative folding of human insulin-like growth factor (IGF)-I yields two major disulphide folding isomers. In the present study, B-domain analogues of IGF-I were used to investigate the effect of mutations on the folding reaction and to investigate the functional implications of misfolding. The analogues used were substitutions of the native Glu3 by Gly or Arg, or the native Glu9 by Lys. IGF-I and these analogues were also prepared attached to a hydrophobic 13-amino-acid N-terminal extension, Met-Phe-Pro-Ala-Met-Pro-Leu-Ser-Ser-Leu-Phe-Val-Asn, referred to as ‘Long-IGF-I’ analogues. Each IGF was fully reduced and refolded to yield native and misfolded isomers, which were subsequently purified for biological characterization. Analysis of the folding reaction at equilibrium revealed a distribution of folding isomers characteristic for each peptide. The yield of the native disulphide folding isomer was increased for the Glu3 substitutions, but not for the Glu9 substitution. The main alternative folding isomer was present in the IGF-I analogues in reduced proportions. Except for [Gly3]IGF-I the N-terminal extension increased the yield of the native isomer which was maximal for the analogue Long-[Arg3]IGF-I. A folding intermediate for the latter analogue was isolated and partially characterized. The biological assays showed that all the main alternative isomers bound poorly to IGF-binding proteins (IGFBPs) secreted by L6 myoblasts. Moreover, these isomers bound to the type 1 IGF receptor with 0.5-25% the affinity of the native isomer. In a rat L6 myoblast protein-synthesis assay, the observed biological activity of the native and main alternative isomers was explained by their modified IGFBP- and receptor-binding properties. We propose that the N-terminal extension imparts a steric constraint at a crucial point in folding, thus allowing native disulphide bonds to form efficiently.

scholarly journals Insulin-Like Growth Factor (IGF) Binding Protein-2, Independently of IGF-1, Induces GLUT-4 Translocation and Glucose Uptake in 3T3-L1 Adipocytes

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Biruhalem Assefa ◽  
Ayman M. Mahmoud ◽  
Andreas F. H. Pfeiffer ◽  
Andreas L. Birkenfeld ◽  
Joachim Spranger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Glucose Uptake ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Glut 4 ◽  
Igf Binding ◽  
Glut 4 Translocation ◽  
Igf Binding Protein ◽  
The Impact

Insulin-like growth factor binding protein-2 (IGFBP-2) is the predominant IGF binding protein produced during adipogenesis and is known to increase the insulin-stimulated glucose uptake (GU) in myotubes. We investigated the IGFBP-2-induced changes in basal and insulin-stimulated GU in adipocytes and the underlying mechanisms. We further determined the role of insulin and IGF-1 receptors in mediating the IGFBP-2 and the impact of IGFBP-2 on the IGF-1-induced GU. Fully differentiated 3T3-L1 adipocytes were treated with IGFBP-2 in the presence and absence of insulin and IGF-1. Insulin, IGF-1, and IGFBP-2 induced a dose-dependent increase in GU. IGFBP-2 increased the insulin-induced GU after long-term incubation. The IGFBP-2-induced impact on GU was neither affected by insulin or IGF-1 receptor blockage nor by insulin receptor knockdown. IGFBP-2 significantly increased the phosphorylation of PI3K, Akt, AMPK, TBC1D1, and PKCζ/λand induced GLUT-4 translocation. Moreover, inhibition of PI3K and AMPK significantly reduced IGFBP-2-stimulated GU. In conclusion, IGFBP-2 stimulates GU in 3T3-L1 adipocytes through activation of PI3K/Akt, AMPK/TBC1D1, and PI3K/PKCζ/λ/GLUT-4 signaling. The stimulatory effect of IGFBP-2 on GU is independent of its binding to IGF-1 and is possibly not mediated through the insulin or IGF-1 receptor. This study highlights the potential role of IGFBP-2 in glucose metabolism.

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