Adapting to multiple personalities: Cbl is also a RING finger ubiquitin ligase

Abstract

Sibyls were prophetesses of the ancient Greek and Roman legends. The Cumaean Sibyl was the best known prophetess who oiered to sell her collection of nine books of prophecies ^ the `Sibylline Books' ^ to the Roman king Tarquinius Prisus. Having been denied her asking price for the collection, the Sibyl sequentially burned six of the nine books until King Tarquin oiered to pay four times the original asking price for the remaining three books. King Tarquin's refusal to purchase the books resulted in the permanent loss of most Sibylline prophecies. Perhaps the lost Sibylline prophecies would have foretold the discovery of Cbl ^ Sibyl's modern-day homonym. Unlike the Sibylline Books where twothirds of the pre-existing information was lost forever, our ¢rst encounter with Cbl began with the discovery of its N-terminal one-third (aa 1^357) in the form of oncogenic v-Cbl, residing in the genome of the Cas NS-1 murine retrovirus [1]. Our understanding of Cbl has since grown at an incredible rate. Not only were the remaining C-terminal two-thirds of Cbl found that were absent in v-Cbl [2], two new Cbl family members [3,4] and their homologues were also discovered in three other species [2,5,6]. We also learned that Cbl possesses a divergent SH2 domain in its N-terminus [7] and that this unusual SH2 domain complex binds to and functions as a negative regulator of receptor and cytoplasmic protein tyrosine kinases (PTK) (reviewed in [8^12]), perhaps by positioning the targeted phosphoproteins in close proximity to the RING ¢nger ubiquitin ligase domain [13]. This review will summarize our current knowledge of Cbl domain structures and their interactions with signaling proteins that may serve as targets or eiectors of Cbl.