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Targetingthecis-dimerizationof LINGO-1 with lowMW compounds affectsits downstreamsignalling Laetitia CobretM.-L. de TauziaJulien Ferent2014 год

Targeting thecis-dimerization of LINGO-1 with low MW compounds affects its downstream signalling
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Аннотация: The transmembrane protein LINGO-1 is a negative regulator in the nervous system mainly affecting axonal regeneration, neuronal survival, oligodendrocyte differentiation and myelination. However, the molecular mechanisms regulating its functions are poorly understood. In the present study, we investigated the formation and the role of LINGO-1 cis-dimers in the regulation of its biological activity. LINGO-1 homodimers were identified in both HEK293 and SH-SY5Y cells using co-immunoprecipitation experiments and BRET saturation analysis. We performed a hypothesis-driven screen for identification of small-molecule protein-protein interaction modulators of LINGO-1 using a BRET-based assay, adapted for screening. The compound identified was further assessed for effects on LINGO-1 downstream signalling pathways using Western blotting analysis and AlphaScreen technology. LINGO-1 was present as homodimers in primary neuronal cultures. LINGO-1 interacted homotypically in cis-orientation and LINGO-1 cis-dimers were formed early during LINGO-1 biosynthesis. A BRET-based assay allowed us to identify phenoxybenzamine as the first conformational modulator of LINGO-1 dimers. In HEK-293 cells, phenoxybenzamine was a positive modulator of LINGO-1 function, increasing the LINGO-1-mediated inhibition of EGF receptor signalling and Erk phosphorylation. Our data suggest that LINGO-1 forms constitutive cis-dimers at the plasma membrane and that low MW compounds affecting the conformational state of these dimers can regulate LINGO-1 downstream signalling pathways. We propose that targeting the LINGO-1 dimerization interface opens a new pharmacological approach to the modulation of its function and provides a new strategy for drug discovery.
Год издания: 2014
Авторы: Laetitia Cobret, M.-L. de Tauzia, Julien Ferent, Élisabeth Traiffort, Imène Sarah Hénaoui, Fabienne Godin, Esther Kellenberger, Didier Rognan, Jacques Pantel, Hélène Benedetti, Séverine Morisset‐Lopez
Издательство: Wiley
Источник: British Journal of Pharmacology
Ключевые слова: Cell Adhesion Molecules Research, Protein Tyrosine Phosphatases
Другие ссылки: British Journal of Pharmacology (PDF)
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Europe PMC (PubMed Central) (PDF)
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