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bioRxiv · 10.1101/2023.02.25.530040

Control of human pancreatic beta cell kinome by GLP-1R biased agonism

Xiao, J.·Eleid, L.·Buenaventura, T.·Boutry, R.·Bonnefond, A.·Jones, B.·Rutter, G. A.·Froguel, P.·Tomas, A.
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Abstract

AimTo determine the kinase activity profiles of human pancreatic beta cells downstream of GLP-1R balanced versus biased agonist stimulations. Materials and methodsThis study analysed the kinomic profiles of human EndoC-{beta}h1 cells following vehicle and glucagon-like peptide-1 receptor (GLP-1R) stimulation with the pharmacological agonist exendin-4, as well as exendin-4-based biased derivatives exendin-phe1 and exendin-asp3 for acute (10-minute) versus sustained (120-minute) responses, using PamChip(R) protein tyrosine kinase (PTK) and serine/threonine kinase (STK) assays. The raw data were filtered and normalised using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. ResultsThe present analysis reveals that kinomic responses are distinct for acute versus sustained GLP-1R agonist (GLP-1RA) exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP-1R signalling mediators, constituting potential targets for further research on biased GLP-1R downstream signalling. ConclusionResults from this study suggest that differentially biased exendin-phe1 and exendin-asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti-T2D therapies with optimised downstream kinomic profiles.

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Xiao, J., Eleid, L., Buenaventura, T., Boutry, R., Bonnefond, A., Jones, B., Rutter, G. A., Froguel, P., Tomas, A.. 2023-02-26. Control of human pancreatic beta cell kinome by GLP-1R biased agonism. https://doi.org/10.1101/2023.02.25.530040

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