Epidermal growth factor receptor signaling.

Abstract

Inhibitory signaling is an important way of fine tuning EGFR activity to enable a cell to discriminate between short and prolonged exposure to signaling molecules. Over the last few years a number of different mechanisms have been shown to abrogate receptor activity (Fig. 3Fig. 3). First, inhibitory signaling molecules are expressed in response to EGFR activation. The most prominent example is encoded by the Drosophila gene argos. Argos is a secreted molecule that has a single EGF-like domain with an expanded B-loop. Binding experiments showed that Argos binds directly to the EGFR presumably via its EGF-like domain and inhibits EGFR activity. Argos prevents Spitz binding and may also interfere with ligand-independent activation of the EGFR by preventing the formation of active EGFR dimers.Fig. 3Negative regulators of EGFR signaling. Several proteins were found to attenuate EGFR signaling. Argos, Decorin, and Kekkon bind to the extracellular domain of the EGFR. PKC is able to phosphorylate the EGFR at T654. Binding of Cbl at Y1045 results in ubiquitination and subsequent degradation. The recently identified Echinoid protein interferes with EGFR signaling downstream. LRR, leucine-rich repeat; Ig, immunoglobulin-like domain; FnIII, fibronectin type III repeat.View Large Image | View Hi-Res Image | Download PowerPoint SlideBesides Argos a number of other molecules attenuate EGFR activity. Again Drosophila has been a powerful system for identifying new components which can inhibit EGFR. Kekkon, which is expressed in response to EGFR activity, encodes a type I transmembrane protein and resembles cell adhesion molecules. The extracellular domain of Kekkon binds to the EGFR and provides a mechanism for negative-feedback. Two additional Kekkon-like proteins are encoded by the Drosophila genome which await characterisation.The Echinoid protein shows identity to the L1 adhesion protein and defines an additional pathway for antagonizing EGFR activity downstream of the receptor. EGFR activity can also be influenced by components of the extracellular matrix. One example is the leucine-rich proteoglycan Decorin that can bind EGFR and attenuate EGFR phosphorylation.sprouty and the cbl are genes which encode global inhibitors of EGFR signaling. Sprouty contains a conserved cysteine-rich domain and associates with components of the EGFR signaling cascade such as Grb2/Drk and GAP1. The function of Sprouty is, however, not restricted to the EGFR pathway. Cbl contains an unusual SH2 domain that is responsible for EGFR binding via Y1045. This interaction leads to the phosphorylation of Cbl, which may facilitate the ubiquitin ligase activity of the Cbl RING finger domain. Ubiquitination of the EGFR leads to its internalization via clathrin-coated vesicles and subsequent degradation.In summary, EGFR signaling appears to be integrated in a complex regulatory network linking extracellular signals to the cytoplasm and the nucleus. In the last decade the modulation of EGFR activity by negative regulators has become more and more evident. Now the picture is getting even more complicated by the fact that differential trafficking of activated EGFR may lead to different cellular responses. Further studies may not only help to increase our understanding of the role of EGFR signaling in the developing animal, they may ultimately lead to the development of efficient anti-cancer therapeutics.