Mechanisms of ErbB receptor negative regulation and relevance in cancer

Abstract

The ErbB family of receptor tyrosine kinases engages a wide variety of signaling pathways that collectively direct transcriptional programs controlling organogenesis during development and tissue maintenance in the adult. These receptors are also frequently found overexpressed or aberrantly activated in various cancers, suggesting that ErbB receptor signaling activity must be very tightly regulated. Sufficient levels of ErbB signaling are necessary to mediate tissue homeostasis, for example, but over-signaling can trigger cellular processes that contribute to cancer initiation or progression. Efforts over the last quarter century have led to a thorough understanding of the signaling pathways that are activated by these receptors and the mechanisms by which ErbB receptors engage these pathways. However, the compensatory negative regulatory mechanisms responsible for attenuating receptor activation have only more recently begun to be explored. Here we review the different known mechanisms of ErbB negative regulation, with particular emphasis on those proteins that exhibit some specificity for the ErbB family. We also describe how loss or suppression of ErbB negative regulators may contribute to tumor development, and discuss how restoration or augmentation of these pathways may represent a novel avenue for the development of ErbB-targeted therapies.

Figure 1

Negative regulators suppress ErbB activation and alter trafficking to attenuate receptor activity. Depicted are ErbB receptors (orange) undergoing ligand-dependent (black arrows) and -independent (purple arrows) trafficking to the sorting endosome from the plasma membrane. At the sorting endosome receptors are trafficked to the lysosome (red arrow) if ubiquitinated, or returned to the cell surface via recycling endosomes (green arrows) if not. The negative regulators characterized thus far act at four general steps in the ErbB life cycle. 1) Argos and p85-s-ErbB3 both sequester activating ligand away from receptors, consequently reducing receptor activation, while 2) Herstatin, Lrig1, Decorin and RALT all directly bind to receptors to suppress their stimulation. 3) Ligand-dependent internalization of receptors into early endosomes leads to the direct recruitment of Cbl to phosphorylated EGFR, followed by Cbl-mediated receptor ubiquitination, while Nrdp1 and SOCS4/5 protein levels are increased in response to ligand binding to mediate the ubiquitination of ErbB3/4 and ErbB1/2/4 respectively. 4) Lrig1, Decorin, Chip, Lnx1, Nrdp1, and SOCS4/5 mediate the ligand-independent degradation of receptors (see text for receptor specificity), with Chip, Lnx1, Nrdp1, and SOCS directly mediating receptor ubiquitination. Negative regulator proteins listed in black act extracellularly, while those listed in blue act cytosolically. Overall, reversible negative regulators such as p-85-s-ErbB3 and Herstatin act early in the signaling pathway to control receptor activation, while ubiquitin ligases such as Cbl and Nrdp1 direct receptors away from the default recycling pathway to the lysosome for the irreversible process of ubiquitin-mediated degradation.