Secondary Dimerization between Members of the Epidermal Growth Factor Receptor Family

Abstract

Growth factor receptors of the epidermal growth factor (EGF) receptor family play pivotal roles in the regulation of cell proliferation and differentiation and are involved in the development of human cancers. It has been well documented that these receptors undergo growth factor-stimulated homo-and heterodimerization as a first step in the initiation of signaling cascades. Here we provide evidence for a new mechanism for growth factor-stimulated receptor dimer formation, designated secondary dimerization. The growth factor-induced dimerization and ensuing receptor trans-autophosphorylation results in the dissociation of the original (primary) receptor dimer. Each phosphorylated receptor monomer then interacts with a new (nonphosphorylated) receptor to form a secondary dimer. Treatment of cells with EGF yields Neu-ErbB3 secondary dimers, and heregulin treatment induces the formation of Neu-EGF receptor (secondary) dimers. The ability of EGF and heregulin to stimulate a cascade of dimerization events points to a novel mechanism by which multiple signaling activities and diverse biological responses are initiated by members of the EGF receptor family.

The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin

“…Similar to the EGF-induced activation of an ErbB-2/ErbB-3 combination we observed in epithelial and in myeloid cells, a recent report described an analogous phenomenon in pheochromocytoma cells (PC12) (Gamett et al, 1997). However, by using ErbB-speci®c tyrosine kinase inhibitors, and relatively high cell and ligand concentrations, these authors concluded that an ErbB-1/ErbB-2 heterodimer precedes formation of the secondary ErbB-2/ErbB-3 heterodimer.…”

“…Together with the observation that this heterodimer is endowed with an increased a nity to NDF (Sliwkowski et al, 1994), our results imply that ligand promiscuity may be a component that contributes to the oncogenic potential of this complementary receptor combination. Importantly, the ability of EGF to stimulate an ErbB-2/ErbB-3 heterodimer has been recently reported by another group, and led to the interpretation that secondary dimerization (ErbB-2/ErbB-3) follows dissociation of a primary ErbB-1-containing receptor dimer (Gamett et al, 1997). Because we demonstrate direct and cooperative interaction of EGF with the ErbB-2/ ErbB-3 heterodimer, our results favor an alternative to the secondary dimerization model.…”

The relative role of ErbB1–4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells

“…The cytoplasmic, COOH-terminal portions of the receptors carry Tyr, Ser, and Thr residues, the phosphorylation states of which are critical for their signaling functions (Earp et al, 1995;Qian et al, 1994;Riese and Stern, 1998). Receptor dimerization upon GF binding results in activation of EGF receptor (ErbB1) and other ErbB species seen as receptor phosphorylation at de®ned Tyr residues through intrinsic kinase activity (Earp et al, 1995;Gamett et al, 1997;Graus-Porta et al, 1997;Riese and Stern, 1998). The hierarchy of interactions between the ErbB receptors involves both homo-and heterodimer formation and is determined by the speci®cities of ErbB1, -3, and -4 for de®ned GFs (Earp et al, 1995;Gamett et al, 1997;Graus-Porta et al, 1997;Riese and Stern, 1998).…”

“…Receptor dimerization upon GF binding results in activation of EGF receptor (ErbB1) and other ErbB species seen as receptor phosphorylation at de®ned Tyr residues through intrinsic kinase activity (Earp et al, 1995;Gamett et al, 1997;Graus-Porta et al, 1997;Riese and Stern, 1998). The hierarchy of interactions between the ErbB receptors involves both homo-and heterodimer formation and is determined by the speci®cities of ErbB1, -3, and -4 for de®ned GFs (Earp et al, 1995;Gamett et al, 1997;Graus-Porta et al, 1997;Riese and Stern, 1998). Based on current information, only ErbB1 and ErbB4 express both GF binding and functional cytoplasmic kinase domains.…”

The ERBB3 receptor in cancer and cancer gene therapy

“…113 ERBB2 participates in communications between ERBB3 and the EGFR: stimulation of PC12 cells with either EGF or NRG led to formation of complexes containing EGFR, ERBB2 and ERBB3; it was proposed that primary dimers of EGFR/ERBB2 after EGF and of ERBB3/ ERBB2 after NRG underwent dissociation, and secondary dimers formed of ERBB2/ERBB3 or ERBB2/EGFR, respectively. 114 A site-specific mutagenesis study identified ERBB2 sites L295 and H296 as critical to ERBB2/ERBB3 heterodimerization in response to NRG. 55 A monoclonal antibody to the EGFR stimulated the growth of NSCLC line PC-14 by enhancing ERBB2/ERBB3 heterodimerization, possibly by blocking hetero-dimerization of EGFR with ERBB2 or ERBB3.…”