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

Eva Szegezdi, Almer M. Van Der Sloot, Devalingam Mahalingam, Lynda O'Leary, Robbert H. Cool, Inés G. Muñoz, Guillermo Montoya, Wim J. Quax, Steven De Jong, Afshin Samali*, Luis Serrano

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish (US)
JournalMolecular and Cellular Proteomics
Volume11
Issue number3
DOIs
StatePublished - Mar 2012

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology

Fingerprint Dive into the research topics of 'Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: Apoptosis induction by TRAIL'. Together they form a unique fingerprint.

Cite this