Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research

Abstract

The EGF receptor (EGFR) and HER2 are members of a growth factor receptor family. Overexpression of either protein in advanced breast cancer correlates with poor prognosis. EGF stimulates growth by binding to EGFR, activating the receptor's intracellular tyrosine kinase. The initial consequence is phosphorylation of specific tyrosine-containing sequences in the receptor's carboxyl terminus. These phosphotyrosines serves as high affinity recognition sites for proteins that, in turn, transmit the growth signal inside the cell. Mechanistic studies suggest that EGF binds to a single EGFR, triggering dimerization with another like receptor molecule. This dimerization is thought to initiate the tyrosine kinase activation. The EGF receptor family was recently expanded with the sequencing of HER3 and HER4. Each of the four family members was postulated to regulate a unique growth or differentiation signaling repertoire when activated by a receptor-specific ligand. However, new data from numerous laboratories suggest that EGFR family members may play a complex and ultimately more flexible role in signaling by forming heterodimers between family members, e.g. EGFR:HER2 or HER4:HER2. These heterodimers may form even when only one member of the pair binds its ligand. This review summarizes current work on heterodimerization and attempts to predict the consequences for downstream signaling. In brief, when compared to ligand-dependent receptor homodimers comprised of two proteins with the same internalization sequence and phosphorylated tyrosine residues, heterodimers are likely to: i) expand substrate selection and downstream signaling pathway activation; ii) promote interaction between sets of substrates in the mixed receptor complexes that would not ordinarily be physically juxtaposed; iii) alter the duration of receptor signaling by changing rates of receptor internalization, ligand loss, kinase inactivation, recycling, etc.; and iv) alter rates of receptor and substrate dephosphorylation. In addition to understanding interactions of heterodimers with the internalization machinery, identification of receptor-specific substrates and binding proteins for each EGFR family member will be necessary to explicate the role of heterodimers in growth and differentiation.

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

“…We hypothesise, however, that there may be a role for c-erbB3 and cerbB4 in tumour di erentiation, based on indirect evidence of similar high levels of c-erbB3 expression in normal breast ducts and/or lobules as in tumour cells of ER positive cancers. We believe the results of the present study do not support the view that overexpression of any member of the type I tyrosine kinase receptor family can potentially enhance steroidautonomous tumour proliferation (Earp et al, 1995) and thus endocrine insensitivity.…”

Chromogenic In Situ Hybridization: A Novel Approach to a Practical and Sensitive Method for the Detection of HER2 Oncogene in Archival Human Breast Carcinoma

“…Thus, this CISH technique seems to be sensitive and specific for detection of HER2 amplification in human archival tumor samples. However, HER2 is a growth factor, and enhanced transcription in the absence of gene amplification is a well-recognized mechanism for cellular function through enhanced production of mRNA by phosphorylation of tyrosine kinase acting on growth factors and regulators of cell growth and proliferation (Earp et al, 1995;Pauletti et al, 1996). Thus, discordances between HER2 overexpression and amplification may simply reflect this fact.…”

Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu

“…Homodimerization of HER2/neu or heterodimerization of HER2Ineu with c-erbB-3 or c-erbB-4 has recently been found to be required for signal transduction after the binding of heregulin to c-erbB-3 or c-erbB-4 (Earp et al, 1995;Wallasch et al, 1995). The possibility that divalent binding of two HER2/neu molecules by C6.5 diabody facilitates the homodimerization of HER2/neu with subsequent signal transduction is intriguing.…”