Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions.

Abstract

The ErbB family includes two receptors, ErbB‐1 and ErbB‐3, that respectively bind to epidermal growth factor and Neu differentiation factor, and an orphan receptor, ErbB‐2. Unlike ErbB‐1 and ErbB‐2, the intrinsic tyrosine kinase of ErbB‐3 is catalytically impaired. By using interleukin‐3‐dependent cells that ectopically express the three ErbB proteins or their combinations, we found that ErbB‐3 is devoid of any biological activity but both ErbB‐1 and ErbB‐2 can reconstitute its extremely potent mitogenic activity. Transactivation of ErbB‐3 correlates with heterodimer formation and is reflected in receptor phosphorylation and the transregulation of ligand affinity. Inter‐receptor interactions enable graded proliferative and survival signals: heterodimers are more potent than homodimers, and ErbB‐3‐containing complexes, especially the ErbB‐2/ErbB‐3 heterodimer, are more active than ErbB‐1 complexes. Nevertheless, ErbB‐1 signaling displays dominance over ErbB‐3 when the two receptors are coexpressed. Although all receptor combinations activate the mitogen‐activated protein kinases ERK and c‐Jun kinase, they differ in their rate of endocytosis and in coupling to intervening signaling proteins. It is conceivable that combinatorial receptor interactions diversify signal transduction and confer double regulation, in cis and in trans, of the superior mitogenic activity of the kinase‐defective ErbB‐3.

Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

“…The mechanism of type I receptor homo or heterodimerization resulting from HRG binding in human epithelial as well as neural cells is currently the subject of intense investigation. There is an evolving consensus indicating that the HER-2/neu receptor may play a critical role in heregulin-induced RTK I signal transduction (Carraway III et al, 1995;Pinkas-Kramarski et al, 1996;Lewis et al, 1996). The related biologic activities of HRG and HER-2 are supported by experiments in which these genes were either knocked out and/or mutated in mice, resulting in similar embryonic heart malformation and defects in the development of the neural system, causing embryonic death at day 11 (Meyer and Birchmeier, 1995;Lee et al, 1995).…”

“…Heregulin has been reported to have a growth stimulatory e ect on the HER-2/neu overexpressing breast cancer cell line SK-BR-3 (Holmes et al, 1992), as well as on HC11 mammary epithelial cells (Marte et al, 1995), mouse ®broblasts transfected with HER-2/neu and HER-3 (Carraway III et al, 1995) and 32D murine hematopoietic cells transfected with di erent RTK I combinations (Pinkas-Kramarski et al, 1996). Conversely, NDF has been reported as a growth inhibitory and di erentiation-promoting factor in MDA-MB-453 and AU-565 mammary carcinoma cells Bacus et al, 1993), as well as an inducer of apoptosis of breast epithelial cells (Daly et al, 1997).…”

Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation

“…Two other members of the ErbB family, ErbB-1 (also called EGF-receptor) and ErbB-2, function as co-receptors, whose recruitment into . Inter-receptor interactions generate a complex network that enables diversification and more stringent control of NDF signaling (Riese et al, 1995;Pinkas-Kramarski et al, 1996). In addition to their di erential heterodimeric preferences, the two NDF receptors di er in their selection of cytoplasmic signaling proteins containing Src homology 2 (SH2) domains .…”

“…However, the most signi®cant di erence is the catalytic tyrosine kinase function, which is practically inactive in ErbB-3, but intact in ErbB-4 (Guy et al, 1994). Therefore, homodimers of ErbB-3 are biologically inactive but their function may be reconstituted by a co-expressed ErbB-1 or ErbB-2 (Riese et al, 1995;Pinkas-Kramarski et al, 1996). ErbB-2, the most oncogenic member of the family, has no known ligand, but by decelerating ligand dissociation, it functions as a shared signaling subunit of all direct receptors (Graus-Porta et al, 1995;Karunagaran et al, 1996).…”

The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients

“…Epidermal growth factor receptors are commonly active in a dimeric form and interaction between different EGF receptor pairs represents a mechanism for signal diversification and amplification (Olayioye et al, 2000;Yarden and Sliwkowski, 2001). Various dimeric pairs depend on the concentration of receptors, the concentration of particular ligands and the affinity of the receptors towards each other (Pinkas-Kramarski et al, 1996;Tzahar et al, 1997). Ligands binding the EGF family receptors induce receptor homo-or heterodimerisation, which involves an array of a number of homodimeric and heterodimeric combinations (Burden and Yarden, 1997).…”