Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3.

Abstract

Amplification and/or overexpression of HER2/neu and HER3 genes have been implicated in the development of cancer in humans. The fact that these receptor tyrosine kinases (RTKs) are frequently coexpressed in tumor‐derived cell lines and that heterodimers form high affinity binding sites for heregulin (HRG) suggests a novel mechanism for signal definition, diversification or amplification. In cells expressing HER2 and HER3, tyrosine phosphorylation of HER3 is markedly increased upon exposure to recombinant HRG. ATP binding site mutants of HER2 and HER3 demonstrate transphosphorylation of HER3 by HER2, but not vice versa. HRG‐induced transphosphorylation of HER3 results in a substrate phosphorylation pattern distinct from HER2 cells and enhances association of the receptor with SHC and phosphoinositol 3‐kinase in transfected 293 and mammary carcinoma‐derived MCF‐7 cells. The physiological relevance of HER2/HER3 heterodimerization is demonstrated by HRG‐dependent transformation of NIH 3T3 cells coexpressing the two receptors. These findings demonstrate the acquisition of expanded signaling capacities for HER2 by HRG‐induced heterodimerization with HER3 and provide a molecular basis for the involvement of receptor heteroactivation in the development of human malignancies.

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

“…Consistent with this notion, neuregulin-mediated proliferation of keratinocytes (Danilenko et al, 1995;Marikovsky et al, 1995), mammary cells (Holmes et al, 1992) and Schwann cells correlates with coexpression of ErbB-2 together with ErB-3, rather than with ErbB-4. Thus, ErbB-3 action may be restricted to cell proliferation, in agreement with the potent mitogenic activity of this receptor in normal (PinkasKramarski et al, 1996) and in tumor cells (Alimandi et al, 1995;Wallasch et al, 1995). However, fatedetermining processes, that do not involve mitosis, may be associated with ErbB-4, whose signaling capacity is rather limited.…”

c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer

“…These data suggest that c-erbB3, and possibly c-erbB4, are involved in aspects of tumour cell di erentiation, rather than in directing cellular growth patterns. Furthermore, although our study does not address the transforming ability of c-erbB3 (or cerbB4), which has previously been shown to be greatly enhanced by the co-expression with c-erbB2 or EGFR in ®broblasts (Alimandi et al, 1995;Wallasch et al, 1995), the detection of c-erbB3 (mRNA and protein) in endocrine sensitive cancers at levels equivalent to those seen in normal breast tissue (albeit cancer associated) would not support a direct transforming role for cerbB3.…”

Cross-talk between the proto-oncogenes Met and Ron

“…ErbB2 by itself is not able to e ciently induce PI3-kinase activation (Peles et al, 1992), but when co-expressed with ErbB3, PI3-kinase activity is strongly increased. This is due to the e cient ErbB2-mediated transphosphorylation of ErbB3, which supplies phosphorylation sites for PI3-kinase (Wallasch et al, 1995).…”