Endocytic Trafficking of the Epidermal Growth Factor Receptor in Transformed Cells

Abstract

The epidermal growth factor receptor (EGFR) is the prototypical receptor tyrosine kinase. It is localized to the plasma membranes of cells with an extracellular ligand binding domain and an intracellular kinase domain. Through the binding of extracellular ligands, the receptor undergoes a conformational change that alters the biochemical properties of proteins (effectors) within the cell. Ultimately, these changes result in modulation of the rate of cell growth, protein and DNA synthesis, cell motility, and cell proliferation. The EGFR is necessary for the proper development of organisms, as indicated by the fact that genetic knockout of the receptor results in animals that are embryonic lethal or die shortly after birth. This developmental role is also observed in adult animals, as pharmacological inhibition of the EGFR disrupts tissue homeostasis. In addition to these developmental roles, there is a strong association between overexpression and/or hyperactivation of the EGFR and cancer. Currently, there are several small molecule inhibitors and neutralizing, humanized antibodies against the EGFR that successfully treat EGFR-positive cancers (i.e. non-small cell lung carcinomas, colon, and head and neck cancers). Breast cancer is among those cancers that are characterized by enhanced EGFR levels and activity. However, the aforementioned pharmacologic agents have been of little success in the treatment of breast cancers. Therefore, a more detailed understanding of the cellular and molecular biology of EGFR function is required in order to successfully attenuate the growth and metastasis of EGFR-positive cells. Cells have numerous endogenous mechanisms to that regulate the specificity and duration of EGFR signaling. Endogenous regulatory mechanisms are logical pharmacological targets to inhibit EGFR activity because of their intrinsic ability to modulate signaling. One of the most important regulators of EGFR signaling is the endocytic pathway. The endocytic pathway can control both the duration of signaling and the spatial placement of the receptor. Historically, endocytosis has been considered a mechanism for the negative regulation of EGFR, as it decreases the number of cell surface receptors and inactivates the ligand:receptor complex by targeting it for lysosomal degradation. More recently, it has been appreciated that signaling of the EGFR varies based on the subcellular localization of the receptor. Specifically, in a given cell, the liganded EGFR can promote cell proliferation at some cellular locations (i.e. plasma membrane), whereas at others (i.e. the limiting membranes of endosomes) the receptor can induce apoptosis. Thus, a potential molecular etiology of EGFR overexpression in transformed cells is disrupted normal endocytic