ADAMs: key components in EGFR signalling and development

Abstract

ADAMs are a family of membrane-anchored glycoproteins that contain a metalloprotease and a disintegrin domain. They have been implicated in fertilization, heart development, angiogenesis, neurogenesis and cancer, and can function as post-translational regulators of other membrane proteins including growth factors such as transforming growth factor (TGF)α and heparin-bound epidermal growth factor (HB-EGF), cytokines such as tumour necrosis factor α (TNFα), and receptors such as Notch and TNF receptor-I. About half of the currently known ADAMs have a catalytic-site consensus sequence (HEXXH), and many of these ADAMs have also been shown to possess catalytic activity. The remaining ADAMs lack a catalytic site in their otherwise conserved metalloprotease-like domain. This review focuses on catalytically active ADAMs, which can function as molecular signalling switches by cleaving and releasing the ectodomain of other membrane proteins. This process, which is referred to as 'protein ectodomain shedding', might activate or inactivate the substrate protein, or dramatically change its functional properties. The EGF-receptor ligands TGFα, HB-EGF and amphiregulin are excellent examples of membrane proteins that are regulated by ectodomain shedding. Biochemical and cell-biological studies, as well as the analysis of knockout mice, have uncovered a key role for ADAM17 (which is also referred to as TNFα-converting enzyme (TACE)) in activating these growth factors during mouse development and potentially also in diseases such as cancer. The EGF receptor has an unusual mechanism of dimerizing compared with other tyrosine kinase receptors, which might explain why signalling through this receptor is particularly sensitive to proteolytic processing of its ligands. ADAMs also have important roles in heart development, angiogenesis and pathological neovascularization. This raises questions about the role of shedding in regulating the function of membrane proteins that are involved in these processes, such as ErbB2, vascular endothelial growth factor receptor-2 (VEGFR2), TIE2, ephrinB2 or EphB2.