ABSTRACT
E3 ubiquitin ligases are the components of the ubiquitin (Ub) system that confer specificity to the covalent attachment of Ub to substrates. Most RING finger (RNF)-containing proteins examined to date exhibit E3 activity. There are nearly 300 genes encoding RNF-containing proteins in the human genome, potentially comprising the largest family of E3s. In this chapter, we examine the evidence that led to the discovery of a functional role for the RNF domain in ubiquitylation, and in particular we describe the thinking processes behind our own work demonstrating that c-Cbl and other RNF-containing proteins act as E3s. For specific references, please consult the following reviews covering the topics referred to here: Thien and Langdon (Nat. Rev. Mol. Cell Biol 2:294) and Pickart (Annu. Rev. Biochem 70:503).
