The EGF/ErbB Receptor Family and Apoptosis

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The ErbB receptor family can activate a multitude of cell signaling pathways that involve many aspects of cellular function. The four members of the ErbB receptor family interact with diverse ligands and substrates, as well as with each other through cell surface heterodimerization. The sum of these diverse interactions is a signaling network that is complex but also finely regulated. Among the cellular functions influenced by ErbB signaling is cell survival. ErbB receptor signaling has been demonstrated to interact with all of the major mechanisms of cell death signaling in a manner that promotes cell survival. Survival factors such as Ras, PI3-K, Akt, and Bcl-x/-2 all have been shown to be activated by ErbB signaling (Fig. 5). ErbB abrogation of apoptotic signals has been shown to play an important role during embryonic tissue development, in normal adult tissue maintenance (e.g. mammary tissue, wound healing), and also in tumor development and progression. Although the majority of studies suggest that ErbB receptor family members are mediators of cell survival, there have been occasional reports suggesting that ErbB receptors can induce cell death under selected experimental conditions. While this apparent discrepancy remains unresolved, in many of these reports, cell death may be the result of anoikis in response to changes in the cytoskeleton associated with hyperstimulation of ErbB signaling. The notion that ErbB receptor family members function to promote cell survival is not a recent observation. However, how this family functions to prevent apoptosis is an area that only recently has been considered. The understanding of ErbB receptor signaling as it relates to the avoidance of apoptosis had profound implications for the treatment of solid tumors originating in multiple tissues, as well as for the treatment of neurodegenerative disease. Further elucidation of the complex relationships between ErbB receptor signaling networks and the apoptotic machinery is certain to yield biologically important and potentially life-saving information.