NDF/heregulin stimulates the phosphorylation of Her3/erbB3

Her3/erbB3 has been identified as a third member of the epidermal growth factor receptor (EGFR) family [(1989) Proc. Natl. Acad. Sci. USA 86, 9193-9197; (1990) Proc. Natl. Acad. Sci. USA 87, 4905-4909]. The natural ligand for Her3 has not been identified. Although recently NDF has been proposed as a specific ligand for Her4 [(1993) Nature 366, 473-475; (1993) J. Biol. Chem. 268, 18407-18410], we report here that Her3 was phosphorylated on tyrosine not only in three breast carcinoma cell lines, MDAMB453, MDAMB468 and SKBR3, but also in Her3-transfected CHO cells in response to NDF stimulation. In further studies, cells were reacted with 125I-labeled NDF and then chemically crosslinked. Immunoprecipitation with anti-Her3 revealed a dense high Mw band, greater than 400 kDa. The results suggest that NDF may be a ligand of Her3 and induces receptor hetero-oligomerization.