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Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: Apoptosis induction by TRAIL

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dc.contributor.author Szegezdi, Eva
dc.contributor.author Mahalingam, Devalingam
dc.date.accessioned 2012-02-17T17:08:10Z
dc.date.available 2012-02-17T17:08:10Z
dc.date.issued 2012
dc.identifier.citation Szegezdi, E.,van der Sloot, A. M.,Mahalingam, D.,O'Leary, L.,Cool, R. H.,Munoz, I. G.,Montoya, G.,Quax, W. J.,de Jong, S.,Samali, A.,Serrano, L. (2012) 'Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: Apoptosis induction by TRAIL'. Mol Cell Proteomics, . en_US
dc.identifier.issn 1535-9484 (Electronic) 15
dc.identifier.uri http://hdl.handle.net/10379/2584
dc.description.abstract Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of non-productive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor-specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using proteins therapeutics could be achieved simply by altering specificity.Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of non-productive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor-specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using proteins therapeutics could be achieved simply by altering specificity. en_US
dc.format application/pdf en_US
dc.language.iso en en_US
dc.publisher American Society for Biochemistry and Molecular Biology en_US
dc.relation.ispartof Mol Cell Proteomics en
dc.subject Apoptosis en_US
dc.subject Death receptor en_US
dc.subject Mathematical modeling en_US
dc.subject Receptor activation kinetics en_US
dc.subject Tumor necrosis factor-related apoptosis-inducing ligand en_US
dc.title Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: Apoptosis induction by TRAIL en_US
dc.type Article en_US
dc.date.updated 2012-02-16T15:13:34Z
dc.local.publishedsource http://www.mcponline.org/content/early/2012/01/02/mcp.M111.013730.short en_US
dc.local.publisherstatement This research was originally published asSzegezdi, E.,van der Sloot, A. M.,Mahalingam, D.,O'Leary, L.,Cool, R. H.,Munoz, I. G.,Montoya, G.,Quax, W. J.,de Jong, S.,Samali, A.,Serrano, L. (2012) 'Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: Apoptosis induction by TRAIL'. Mol Cell Proteomics, . © the American Society for Biochemistry en_US
dc.description.peer-reviewed peer-reviewed
dc.contributor.funder |~|
dc.internal.rssid 1301398
dc.local.contact Eva Erzsebet Szegezdi, Biochemistry, Arts/Science Building, Nui Galway. 5038 / 5037 Email: eva.szegezdi@nuigalway.ie
dc.local.copyrightchecked No
dc.local.version ACCEPTED

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