ErbB-2 Amplification Inhibits Down-regulation and Induces Constitutive Activation of Both ErbB-2 and Epidermal Growth Factor Receptors

Abstract

ErbB-2/HER2 is an important signaling partner for the epidermal growth factor receptor (EGFR). Overexpression of erbB-2 is also associated with poor prognosis in breast cancer. To investigate how erbB-2 amplification affects its interactions with the EGFR, we used a human mammary epithelial cell system in which erbB-2 expression was increased 7-20-fold by gene transfection. We found that amplification of erbB-2 caused constitutive activation of erbB-2 as well as ligand-independent activation of the EGFR. Overexpression of erbB-2 strongly inhibited erbB-2 down-regulation following transactivation by EGFR. Significantly, down-regulation of activated EGFR was also inhibited by erbB-2 amplification, resulting in enhanced ligand-dependent activation of the EGFR. The rate of EGFR endocytosis was not affected by erbB-2 overexpression, but the rate of lysosomal targeting was significantly reduced. In addition, erbB-2 overexpression promoted rapid recycling of activated EGFR back to the cell surface and decreased ligand dissociation from the EGFR. Our data suggest that overexpression of erbB-2 inhibits both its downregulation and that of the EGFR. The net effect is increased signaling through the EGFR system.

Expression of epidermal growth factor receptor in squamous cell carcinomas of the anal canal is independent of gene amplification

“…Moreover, heterodimerization with or overexpression of HER2 may potentiate EGFR functioning by increasing EGF-binding affinity, stabilizing EGFR, promoting rapid recycling of EGFR back to the cell surface, and expanding the repertoire of receptor-associated substrates and signaling responses. 43,44 Furthermore, EGFR can 'crosstalk' with additional heterologous receptors activated by a variety of stimuli to amplify its biological activities. 40 In general, EGFR overexpression has been found to be associated with advanced tumor stage and poor prognosis in a number of human malignancies, such as carcinomas of the esophagus, 6 stomach, 45 colorectum, 16,46 bladder, 11 and breast.…”

Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-Terminus

“…The receptor tyrosine kinase ErbB2 is a potent oncoprotein, and a high ErbB2 level can by itself activate ErbB receptors (Worthylake et al, 1999). Concordantly, increased ErbB2 levels can be found in several cancers (Klapper et al, 2000;Yarden, 2001), and high ErbB2 levels are correlated to a worse prognosis for breast cancer patients (Slamon et al, 1987;Hynes and Stern, 1994;De Placido et al, 1998;Pegram et al, 1998).…”

“…Little attention has been paid to the role of ErbB2 degradation in cancers, although when compromised it also would lead to increased ErbB2 levels and activity. Several studies have shown that endocytic downregulation of ErbB2 is impaired in cancer cells (Sorkin et al, 1993; Baulida et al, 1996;Wang et al, 1999;Hommelgaard et al, 2004;Austin et al, 2004;Longva et al, 2005), and ErbB2 can even transmit this property to the related epidermal growth factor receptor (EGFR; Muthuswamy et al, 1999;Wang et al, 1999;Worthylake et al, 1999;Haslekas et al, 2005). Inhibition of HSP90 (e.g., with geldanamycin [GA]) leads to increased internalization and lysosomal degradation of ErbB2 in a manner depending on proteasomal activity (Tikhomirov and Carpenter, 2000;Austin et al, 2004;Lerdrup et al, 2006).…”

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

“…Stimulation of cells with EGF induces the heterodimerization of EGFR with other family members (Alroy and Yarden, 1997). It has been shown that the heterodimerization of EGFR with ErbB2 and ErbB3 inhibits the down-regulation of EGFR (Lenferink et al, 1998;Wang et al, 1999;Worthylake et al, 1999). Therefore, it is possible that UBPY also indirectly regulates the down-regulation of EGFR by controlling the cellular levels of its heterodimerization partners, ErbB2 and/or ErbB3.…”