Previous data have shown that in several tumor cells lines the addition of heregulin results in the translocation of ErbB-4 to a detergent-insoluble membrane fraction where it is hypertyrosine phosphorylated. The data herein demonstrate that heregulin or betacellulin, but not EGF, promotes the rapid translocation of ErbB-2, the heterodimerization partner for ErbB-4, to the same detergent-insoluble fraction in T47 D mammary carcinoma cells. The translocation of ErbB-2 and ErbB-4, but not ErbB-3, to this detergent-insoluble fraction is readily detected 2 min after the addition of heregulin. ErbB-2 present in this detergent-insoluble membrane fraction is tyrosine phosphorylated to a level fourfold greater than the majority of cellular ErbB-2 present in the detergent-soluble membrane fraction. These results suggest the ligand-dependent formation of hyperphosphorylated ErbB-4/ErbB-2 dimers coordinate with translocation to a putative membrane microdomain.