It is established that cytokine receptors signal after ligand binding as homo- or hetero-dimers in heteromeric complexes, but it is unclear, when dimerization occurs. To investigate gp130 dimerization, we performed co-precipitation experiments with the endogenous cytokine receptors gp130 and leukemia inhibitory factor receptor (LIF-R) and with gp130 variants carrying two different C-terminal peptide tags. Furthermore, fluorescence resonance energy transfer (FRET) was employed to detect dimerization of two fluorescent-tagged gp130 variants. Confocal laser scanning microscopy was used for FRET detection in live cells. gp130 and LIF-R could be coprecipitated in the absence of ligand. The interaction, however, was intensified by the addition of LIF. Similar results were obtained with the gp130 variants and confirmed by FRET analysis in live cells. The present study clearly demonstrates the existence of preformed but inactive gp130/LIF-R hetero- and gp130/gp 130 homo-dimers. The addition of ligand enhanced the respective dimer formation and was required for signal transduction. (c) 2006 Elsevier Inc. All rights reserved.