ArticleMolecular & cellular proteomics : MCP2012
Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: apoptosis induction by TRAIL.
Article in Molecular & cellular proteomics : MCP, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Helping Apo2L/TRAIL in the Battle: Synergistic Therapeutic Approaches for Cancer Therapies.International journal of molecular sciences · 2026Review
- Two-level modeling approach to identify the regulatory dynamics capturing drug response heterogeneity in single-cells.Scientific reports · 2021Article
- Death Receptors DR4 and DR5 Undergo Spontaneous and Ligand-Mediated Endocytosis and Recycling Regardless of the Sensitivity of Cancer Cells to TRAIL.Frontiers in cell and developmental biology · 2021Article
- Molecular Mode of Action of TRAIL Receptor Agonists-Common Principles and Their Translational Exploitation.Cancers · 2019Review
- Importance of TRAIL Molecular Anatomy in Receptor Oligomerization and Signaling. Implications for Cancer Therapy.Cancers · 2019Review
- Death receptor 5 is activated by fucosylation in colon cancer cells.The FEBS journal · 2019Article
- Relationship between the agonist activity of synthetic ligands of TRAIL-R2 and their cell surface binding modes.Oncotarget · 2018Article
- Mass Action Kinetic Model of Apoptosis by TRAIL-Functionalized Leukocytes.Frontiers in oncology · 2018Article
- Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity.Oncogene · 2016Article
- TRAIL-receptor preferences in pancreatic cancer cells revisited: Both TRAIL-R1 and TRAIL-R2 have a licence to kill.BMC cancer · 2015Article
- Systems biology of death receptor networks: live and let die.Cell death & disease · 2014Review
- DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer.Cancer biology & therapy · 2014Article
- Nutlin-3 preferentially sensitises wild-type p53-expressing cancer cells to DR5-selective TRAIL over rhTRAIL.British journal of cancer · 2013Article
- Death receptors as targets in cancer.British journal of pharmacology · 2013Review
- The design and characterization of receptor-selective APRIL variants.The Journal of biological chemistry · 2012Article
- Advancing cell biology through proteomics in space and time (PROSPECTS).Molecular & cellular proteomics : MCP · 2012Article
Corrections and comments
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
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 nonproductive 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 protein therapeutics could be achieved simply by altering specificity.
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