ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer.

Abstract

Overexpression of the erbB‐2 gene contributes to aggressive behavior of various human adenocarcinomas, including breast cancer, through an unknown molecular mechanism. The erbB‐2‐encoded protein is a member of the ErbB family of growth factor receptors, but no direct ligand of ErbB‐2 has been reported. We show that in various cells ErbB‐2 can form heterodimers with both EGF receptor (ErbB‐1) and NDF receptors (ErbB‐3 and ErbB‐4), suggesting that it may affect the action of heterologous ligands without the involvement of a direct ErbB‐2 ligand. This possibility was addressed in breast cancer cells through either overexpression of ErbB‐2 or by blocking its delivery to the cell surface by means of an endoplasmic reticulum‐trapped antibody. We report that ErbB‐2 overexpression enhanced binding affinities to both EGF and NDF, through deceleration of ligand dissociation rates. Likewise, removal of ErbB‐2 from the cell surface almost completely abolished ligand binding by accelerating dissociation of both growth factors. The kinetic effects resulted in enhancement and prolongation of the stimulation of two major cytoplasmic signaling pathways, namely: MAP kinase (ERK) and c‐Jun kinase (SAPK), by either ligand. Our results imply that ErbB‐2 is a pan‐ErbB subunit of the high affinity heterodimeric receptors for NDF and EGF. Therefore, the oncogenic action of ErbB‐2 in human cancers may be due to its ability to potentiate in trans growth factor signaling.

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

“…Nevertheless, ErbB-3 and ErbB-4 are not expressed in a mutually exclusive manner. For example, both skeletal muscles (Figure 2d and e) and some epithelia (Figure 1, lower panel) express both receptors in mid-gestation, in line with their co-expression in certain mammary, lung, and other types of epithelial cell lines Karunagaran et al, 1996). Distinct, but partially overlapping, patterns of expression extend also to the heterogenous cell types of brain: whereas dissociated oligodendrocytes express both receptors, neurons and astrocytes appear to contain primarily ErbB-4 ( Figure 5a).…”

“…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). Gene targeting experiments supported this notion and added more functions to the list of neuregulin roles: ErbB-2-de®cient mice (Lee et al, 1995) shared a similar phenotype with both NDF/ neuregulin-knockout animals Kramer et al, 1996), and with ErbB-4-defective mice (Gassmann et al, 1995), in that formation of the heart trabeculae was impaired, causing embryonic lethality.…”

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

“…ErbB-2 has no ligand, but its basal activity is increased by EGF-like ligands. By heterodimerizing with ErbB members, ErbB-2 augments EGF/EGF-like ligand signaling (Karunagaran et al, 1996;Graus-Porta et al, 1997). EGFR promotes pubertal breast ductal morphogenesis in mice, and both EGFR and ErbB-2 are relevant in pathogenesis and behavior of breast and other human cancers (Berger et al, 1988;Xie et al, 1997;Biscardi et al, 2000;Mendelsohn and Baselga, 2000;Stern, 2000;Mendelsohn and Baselga, 2003).…”

RAFTK/Pyk2 tyrosine kinase mediates the association of p190 RhoGAP with RasGAP and is involved in breast cancer cell invasion

“…HRG can activate the ErbB-2 receptor as a result of ErbB-2/ErbB-3 or ErbB-2/ErbB-4 heterodimeric interactions (Karunagaran et al, 1996). HRG can either elicit a growth arrest and di erentiation phenotype resulting in morphological changes, induction of milk component synthesis (caseine and lipids) (Kumar et al, 1996), and expression of intracellular adhesion molecule-1, or induce a mitogenic response, depending on the cell type studied (Sepp-Lorenzino et al, 1996).…”