Specificity in ligand binding and intracellular signalling by insulin and insulin-like growth factor receptors

The physiological roles of insulin and insulin-like growth factors (IGFs) are distinct, with insulin acting to regulate cellular uptake and metabolism of fuels, whereas IGFs promote cell growth, survival and differentiation. The only components of signalling pathways known to be unique to insulin an...

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Bibliographic Details
Published in:	Biochemical Society transactions Vol. 29; no. Pt 4; p. 513
Main Authors:	Siddle, K, Ursø, B, Niesler, C A, Cope, D L, Molina, L, Surinya, K H, Soos, M A
Format:	Journal Article
Language:	English
Published:	England 01-08-2001
Subjects:	Amino Acid Sequence Animals Binding Sites CHO Cells Cricetinae Insulin - physiology Insulin-Like Growth Factor I - physiology Insulin-Like Growth Factor II - physiology Ligands Mammals Mutagenesis, Site-Directed Protein Structure, Secondary Protein Subunits Receptor, IGF Type 1 - chemistry Receptor, IGF Type 1 - physiology Receptor, IGF Type 2 - chemistry Receptor, IGF Type 2 - physiology Receptor, Insulin - chemistry Receptor, Insulin - physiology Recombinant Proteins - chemistry Recombinant Proteins - metabolism Signal Transduction - physiology src Homology Domains Substrate Specificity Transfection
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Summary:	The physiological roles of insulin and insulin-like growth factors (IGFs) are distinct, with insulin acting to regulate cellular uptake and metabolism of fuels, whereas IGFs promote cell growth, survival and differentiation. The only components of signalling pathways known to be unique to insulin and IGFs are their respective receptors, and even these display substantial structural and functional similarity. Specificity of action in vivo must in part reflect relative levels of receptor expression in different tissues. The extent to which the receptors differ in intrinsic signalling capacity remains unclear, but specificity might in principle arise from differences in ligand-binding mechanism or properties of intracellular domains. To identify ligand binding determinants we expressed receptor fragments as soluble proteins. Both N-terminal domains and a C-terminal peptide sequence from the alpha-subunit are essential for ligand binding with moderate affinity. However, binding of ligand with high affinity and specificity requires higher-order structure. To compare signalling capacities, we constructed chimaeras containing intracellular domains of insulin or IGF receptors fused to the extracellular portion of TrkC. Expression and activation of these chimaeras in cell lines reveals subtle differences in signalling and end-point responses, which may depend on cell background.
ISSN:	0300-5127
DOI:	10.1042/BST0290513