Heregulin induces tyrosine phosphorylation of HER4/p180erbB4

THE HER4/ERBB4 gene encodes a 180K transmembrane protein (HER4/pl80erbB4 that is structurally related to the 185K product (HERl/pl85erbB2 of the HER2/ERBB2 proto-oncogene1. A 45K heparin-binding glycoprotein (p45) has been characterized that specifically activates the intrinsic tyrosine kinase activity of HER4 (ref. 2). This HER4 ligand shares several features with the heregulin family of proteins, including molecular mass, ability to induce differentiation of breast cancer cells, activation of tyrosine phosphorylation in MDA-MB453 cells, and amino-terminal protein sequence. Heregulin exists as multiple isoforms and all are presumed to interact directly with HER2 (refs 3–6). We have used binding and phosphorylation studies with recombinant ligand on cell lines expressing recombinant receptors, and report here that heregulin, like p45, is a specific ligand for HER4. Furthermore, heregulin fails to induce phosphorylation of HER2 in the absence of HER4. These findings suggest that activation of the HER4 receptor is involved in signal transduction by heregulin.

[1]  B. Seed,et al.  Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[2]  G. Plowman,et al.  Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[3]  D. Goeddel,et al.  Identification of Heregulin, a Specific Activator of p185erbB2 , 1992, Science.

[4]  Y. Yarden,et al.  Cell‐type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER‐2 suggests complex ligand‐receptor relationships. , 1993, The EMBO journal.

[5]  C. Disteche,et al.  The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity , 1990, Molecular and cellular biology.

[6]  M. Waterfield,et al.  Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system , 1993, Nature.

[7]  A. Ullrich,et al.  Chicken epidermal growth factor (EGF) receptor: cDNA cloning, expression in mouse cells, and differential binding of EGF and transforming growth factor alpha , 1988, Molecular and cellular biology.

[8]  R. Lupu,et al.  Characterization of a growth factor that binds exclusively to the erbB-2 receptor and induces cellular responses. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[9]  R. Lupu,et al.  Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. , 1990, Science.

[10]  R. Koski,et al.  Neu differentiation factor: A transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit , 1992, Cell.

[11]  A. Ullrich,et al.  Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[12]  G. Plowman,et al.  Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor. , 1993, The Journal of biological chemistry.

[13]  William Arbuthnot Sir Lane,et al.  ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family , 1993, Cell.