Negative regulation of ErbB family receptor tyrosine kinases

Abstract

Receptors of the EGF receptor or ErbB family of growth factor receptor tyrosine kinases are frequently overexpressed in a variety of solid tumours, and the aberrant activation of their tyrosine kinase activities is thought to contribute to tumour growth and progression. Much effort has been put into developing inhibitors of ErbB receptors, and both antibody and small-molecule approaches have exhibited clinical success. Recently, a number of endogenous negative regulatory proteins have been identified that suppress the signalling activity of ErbB receptors in cells. These include intracellular RING finger E3 ubiquitin ligases such as cbl and Nrdp1 that mediate ErbB receptor degradation, and may include a wide variety of secreted and transmembrane proteins that suppress receptor activation by growth factor ligands. It will be of interest to determine the extent to which tumour cells suppress these pathways to promote their progression, and whether restoration of endogenous receptor-negative regulatory pathways may be exploited for therapeutic benefit. The ErbB family of receptor tyrosine kinases, consisting of the EGF receptor, ErbB2, ErbB3 and ErbB4, directs a broad range of developmental events and contributes to the malignancy of a number of tumour types. Numerous in vivo and in vitro studies have shown that ErbB signalling plays essential roles in the development and maintenance of mammary, cardiac and neural tissues, and contributes to the development of a variety of other tissues through epithelial remodelling and differentiation. The aberrant activation of ErbB receptors in tumours can occur via mutational activation, receptor overexpression, or through tumour production of autocrine growth factor ligands.Owing to the widespread role of ErbB receptor activation in tumour growth and progression, the development of ErbB inhibitors has been a subject of intense interest. Indeed, neutralising antibodies directed towards the EGF receptor or ErbB2 are either in clinical trials or have received FDA approval for the treatment of some tumours (Arteaga, 2003). Moreover, a variety of small-molecule inhibitors are being developed to target these receptors. In this light, it is of interest to look more closely at endogenous ErbB receptor-negative regulatory pathways, the mechanisms by which tumours could overcome these checks on receptor activity, and whether these mechanisms might be employed to ultimately benefit patients.Members of the mammalian ErbB family are acted upon by EGFlike growth factor ligands, which bind to receptor extracellular domains to stimulate tyrosine kinase activity. The EGF-like domain, a 40 -60 amino-acid domain characterised by six cysteine residues forming three disulphide bonds, is a very common component of the extracellular regions of a variety of proteins encompassing a wide range of functions. Only a small subset of EGF-like proteins function as activating ligands for ErbB receptors. Despite a high degree of sequence similarity, each of the ErbB receptors appears to possess distinct bioc...

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