Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: apoptosis induction by trail
van der Sloot, Almer M.
Cool, Robbert H.
Muñoz, Inés G.
Quax, Wim J.
de Jong, Steven
MetadataShow full item record
This item's downloads: 0 (view details)
Szegezdi, Eva; van der Sloot, Almer M. Mahalingam, Devalingam; O'Leary, Lynda; Cool, Robbert H.; Muñoz, Inés G.; Montoya, Guillermo; Quax, Wim J.; de Jong, Steven; Samali, Afshin; Serrano, Luis (2012). Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: apoptosis induction by trail. Molecular & Cellular Proteomics 11 (3),
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 Molecular & Cellular Proteomics 11: 10.1074/mcp.M111.013730, 1-13, 2012.
Showing items related by title, author, creator and subject.
Mc Cormack, O; Chung, W Y; Fitzpatrick, P; Cooke, F; Flynn, B; Harrison, M; Fox, E; Gallagher, E; Goldrick, A Mc; Dervan, P A; Mc Cann, A; Kerin, M J (Springer Nature, 2008-02-19)Growth arrest- specific gene 6 ( Gas6), identified in 1995, acts as the ligand to the Axl/ Tyro3 family of tyrosine kinase receptors and exerts mitogenic activity when bound to these receptors. Overexpression of the Axl/ ...
The trail-receptor-1: trail-receptor-3 and -4 ratio is a predictor for trail sensitivity of cancer cells Zwacka, (Spandidos Publications, 2009-04-06)The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in many cancer cells. However, a significant proportion of tumours are TRAIL-resistant erecting a major hurdle for a ...
Yu, Rui; Albarenque, Stella Maris; Cool, Robbert H; Quax, Wim J; Mohr, Andrea; Zwacka, Ralf M (Informa UK Limited, 2014-11-20)Current treatment modalities for pancreatic carcinoma afford only modest survival benefits. TRAIL, as a potent and specific inducer of apoptosis in cancer cells, would be a promising new treatment option. However, since ...