title: The transmembrane heregulin precursor is functionally active.
abstract: A variety of eucaryotic polypeptide growth factors are synthesized as transmembrane precursors. Many of these precursors are released from plasma membranes by proteolytic cleavage and converted into soluble mature proteins. A number of studies, however, indicate that bound growth factor precursors can be biologically active, suggesting a role for these membrane-associated ligands in cell-cell communication. Secreted heregulin is a 45-kDa growth factor with homology to epidermal growth factor. This growth factor binds directly to HER-3 and HER-4 and activates heterodimeric receptor complexes composed of the type I receptor tyrosine kinases, i.e. HER-1, HER-2, HER-3, and 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 human breast cells. Transmembrane heregulin binds to cells expressing p180(HER-3), induces p185(HER-2/neu) phosphorylation, and increases DNA synthesis in cells overexpressing the HER-2/neu gene product. In addition, when cells containing heregulin receptors are co-cultured with heregulin-producing cells, specific in vivo associations are observed. This study demonstrates that transmembrane heregulin is functionally active and suggest it is capable of playing a role in cell-cell communication and subsequent signal transduction in vivo.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, California 90024, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Aguilar
authors.forename: D J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000502:physiology*; D020890:Neuregulin-1 / Q000502:physiology*; D010766:Phosphorylation; D011498:Protein Precursors / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D008565:Membrane Proteins; D020890:Neuregulin-1; D011498:Protein Precursors; D018719:Erb-b2 Receptor Tyrosine Kinases; D013936:Thymidine