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dc.contributor.authorSzegezdi, Eva
dc.contributor.authorMahalingam, Devalingam
dc.date.accessioned2012-02-17T17:08:10Z
dc.date.available2012-02-17T17:08:10Z
dc.date.issued2012
dc.identifier.citationSzegezdi, 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.issn1535-9484 (Electronic) 15
dc.identifier.urihttp://hdl.handle.net/10379/2584
dc.description.abstractHere 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.formatapplication/pdfen_US
dc.language.isoenen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.relation.ispartofMol Cell Proteomicsen
dc.subjectApoptosisen_US
dc.subjectDeath receptoren_US
dc.subjectMathematical modelingen_US
dc.subjectReceptor activation kineticsen_US
dc.subjectTumor necrosis factor-related apoptosis-inducing liganden_US
dc.titleKinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: Apoptosis induction by TRAILen_US
dc.typeArticleen_US
dc.date.updated2012-02-16T15:13:34Z
dc.local.publishedsourcehttp://www.mcponline.org/content/early/2012/01/02/mcp.M111.013730.shorten_US
dc.local.publisherstatementThis 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 Biochemistryen_US
dc.description.peer-reviewedpeer-reviewed
dc.contributor.funder|~|
dc.internal.rssid1301398
dc.local.contactEva Erzsebet Szegezdi, Biochemistry, Arts/Science Building, Nui Galway. 5038 / 5037 Email: eva.szegezdi@nuigalway.ie
dc.local.copyrightcheckedNo
dc.local.versionACCEPTED
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