The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors

Abstract

The erbB-2͞HER2 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.Cellular growth and fate determination are controlled by a large variety of extracellular ligands and specific cell surface receptors. The largest family of such receptors is that of the growth factor receptors with intrinsic tyrosine kinase activity (1). Type-1 tyrosine kinase receptors, also known as ErbB͞ HER proteins, comprise one of the better-characterized subfamilies of growth factor receptors, of which the epidermal growth factor (EGF) receptor (ErbB-1) is the prototype (reviewed in ref.2). The four ErbB members form homo-and heterodimeric complexes on binding of EGF-like or neuregulin (NRG) ligands, and, thereby, their kinase activity is stimulated and intracellular signals are generated. Constitutive stimulation of these pathways through autocrine or other mechanisms is associated with several types of human cancer (3). Most relevant is the frequent overexpression, often as a result of gene amplification, of ErbB-2͞HER2 in breast, ovary, lung, and other types of epithelial cancers (reviewed in refs. 4 and 5). In some tissues, this overexpression was correlated with poorer prognosis and a more aggressive tumor phenotype (6).Although ErbB-2 shares extensive structural homology with other ErbBs both along the catalytic intracellular domain and in the extracellular putative ligand binding region, many attempts to identify stimulatory ligands specific to ErbB-2 have so far failed. For example, detection of an activity that enhances ErbB-2 phosphorylation led to molecular cloning of the Neu differentiation factor (NDF) and heregulin, two of a dozen isoforms of NRG1, all of which bind to ErbB-3 and ErbB-4 (7). Nevertheless, several observations imply that ErbB-2 homodime...

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