Abstract
Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B’29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR antagonist, exhibited partial agonistic effects in the 1–10 nM range, showing altogether a bell-shaped dose-response curve. Intriguingly, the agonistic effects of S961 were seen only on mitogenic endpoints (3H-thymidine incorporation), and not on metabolic endpoints (14C-glucose incorporation in adipocytes and muscle cells). The agonistic effects of S961 were observed in 3 independent cell lines, with complete concordance between mitogenicity (3H-thymidine incorporation) and phosphorylation of the IR and Akt. Together with the B29-B’29 crosslinked dimer, S961 is a rare example of a mixed agonist/antagonist for the human IR. A plausible mechanistic explanation based on the bivalent crosslinking model of IR activation is proposed.
Highlights
The insulin receptor (IR) is a member of the receptor tyrosine kinase (RTK) family [1,2,3,4,5,6], which includes the receptors for insulin, insulin-like growth factors (IGFs) and many other growth factors
S961 Stimulated a Mitogenic Response in L6-hIR Cells Usually, in mammalian cells, IGF-I is a stronger mitogen than insulin [20,21]
This was in agreement with a previous report [19], supporting that in L6-hIR cells, the mitogenic effect of insulin is primarily mediated by the transfected human IR
Summary
The insulin receptor (IR) is a member of the receptor tyrosine kinase (RTK) family [1,2,3,4,5,6], which includes the receptors for insulin, insulin-like growth factors (IGFs) and many other growth factors. In order to explain the acceleration of dissociation of prebound labelled insulin by unlabelled insulin (negative cooperativity), De Meyts [8] proposed that IR sites 1 and 2 are disposed in an antiparallel symmetry, allowing alternative crosslinking of the two pairs of binding sites. The authors found that S597 was able to antagonize the effect of insulin on cell proliferation down to the effect of S597 alone, indicating that S597 is not a full but a partial agonist for mitogenesis [17] This prompted us to examine more closely the properties of the site 1–2 peptide S961, nearly identical to S661 [18] reported to be a full IR antagonist, and investigate whether it may have agonistic properties on the IR
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
