Both topoisomerase $II{alpha}$ and $II{eta}$ east as phosphoproteins in the cells. Recently it was reported that DNA topoisomerase $II{alpha}$ associates with and is phosphorylated by the extracellular signal-regulated kinase 2 (ERK2). Also, ERK2 stimulates the activity of topoisomerase II by a phosphorylation-independent manner [Shapiro et al., (1999) Mol. Cell. Biol. 19, 3551-3560]. In this study, a yeast two-hybrid system was used to investigate the binding site between topoisomerase $II{alpha}$ or $II{eta}$ and ERK2. The two-hybrid test clearly showed that topoisomerase $II{eta}$ residues 1099-1263, and topoisomerase $II{alpha}$ residues 1078-1182, mediate the interaction with ERK2, and that the leucine zipper motifs of topoisomerase $II{alpha}$ and $II{eta}$ are not required for its physical binding to ERK2. Our results suggest that topoisomerase $II{eta}$ residues 1099-1263, and topoisomerase $II{alpha}$ residues 1078-1182, may be common binding sites for activator proteins.