The ErbB-2/HER2 Oncoprotein of Human Carcinomas May Function Solely as a Shared Coreceptor for Multiple Stroma-Derived Growth Factors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 9; pp. 4995 - 5000
• Main Authors: Klapper, Leah N., Glathe, Stefanie, Vaisman, Nora, Hynes, Nancy E., Andrews, Glenn C., Sela, Michael, Yarden, Yosef
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 27-04-1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Antibodies; Biological Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Carcinoma - genetics; Carcinoma - metabolism; Carcinoma - pathology; Cell growth; Cell lines; Cellular biology; Epidermal Growth Factor - metabolism; Female; Genes; Genes, erbB-2; Glycoproteins - metabolism; Humans; Ligands; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Myeloid cells; Nerve Growth Factors - metabolism; Neuregulins; Oncogenes; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Phosphorylation; Poxviridae; Proteins; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction; Stromal Cells; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.9.4995

The erbB-2/HER2 oncogene is overexpressed in a significant fraction of human carcinomas of the breast, ovary, and lung in a manner that correlates with poor prognosis. Although the encoded protein resembles several receptors for growth factors, no high affinity ligand of ErbB-2 has so far been fully characterized. However, several lines of evidence have raised the possibility that ErbB-2 can augment signal transduction initiated by binding of certain growth factors to their direct receptors. Here, we contrasted these two models of ErbB-2 function: First, examination of a large series of epidermal growth factor (EGF)-like ligands and neuregulins, including virus-encoded ligands as well as related motifs derived from the precursor of EGF, failed to detect interactions with ErbB-2 when this protein was singly expressed. Second, by using antibodies that block inter-ErbB interactions and cells devoid of surface ErbB-2, we learned that signaling by all ligands examined, except those derived from the precursor of EGF, was enhanced by the oncoprotein. These results imply that ErbB-2 evolved as a shared receptor subunit of all ErbB-specific growth factors. Thus, oncogenicity of ErbB-2 in human epithelia may not rely on the existence of a specific ligand but rather on its ability to act as a coreceptor for multiple stroma-derived growth factors.