The transmembrane heregulin precursor is functionally active

A variety of eucaryotic polypeptide growth factors are synthesized as trans membrane precursors. Many of these precursors are released from plasma memb ranes by proteolytic cleavage and converted into soluble mature proteins. A number of studies, however, indicate that bound growth factor precursors c an be biologically active, suggesting a role for these membrane-associated ligands in cell-cell communication. Secreted heregulin is a 45-kDa growth f actor with homology to epidermal growth factor. This growth factor binds di rectly to HER-3 and HER-4 and activates heterodimeric receptor complexes co mposed of the type I receptor tyrosine kinases, i.e. HER-1 HER-2, HER-3, an d HER-4. Heregulin was originally detected in the conditioned medium of the human breast cancer cell line MDA-MB-231 and purified based on its ability to stimulate phosphorylation of p185(HER-2/neu). In the current study, the biologic activity of plasma membrane-anchored heregulin was evaluated in h uman breast cells. Transmembrane heregulin binds to cells expressing p180(H ER-3), induces p185(HER-2/neu) phosphorylation, and increases DNA synthesis in cells overexpressing the HER-2/neu gene product. In addition, when cell s containing heregulin receptors are co-cultured with heregulin-producing c ells, specific in vivo associations are observed. This study demonstrates t hat transmembrane heregulin is functionally active and suggest it is capabl e of playing a role in cell-cell communication and subsequent signal transd uction in vivo.