proto-oncogene that regulates the p53 tumor suppressor (Fang et al., 2000), and members of the IAP family Ubiquitin-protein ligases (E3s) regulate diverse celluof antiapoptotic proteins (Yang et al., 2000). lar processes by mediating protein ubiquitination. The The c-Cbl protein attenuates signaling by the actic-Cbl proto-oncogene is a RING family E3 that recogvated PDGF, EGF, and CSF-1 receptor tyrosine kinases nizes activated receptor tyrosine kinases, promotes (RTKs) by inducing their ubiquitination and subsequent their ubiquitination by a ubiquitin-conjugating enzyme degradation by the proteasome (Miyake et al., 1998; Joazeiro et al., 1999; Lee et al., 1999; Levkowitz et al., (E2) and terminates signaling. The crystal structure of 1999). c-Cbl also negatively regulates the immune rec-Cbl bound to a cognate E2 and a kinase peptide ceptor-coupled ZAP-70 and Syk tyrosine kinases, but shows how the RING domain recruits the E2. A comit is not known whether it induces their ubiquitination parison with a HECT family E3-E2 complex indicates (Lupher et al., 1997; Ota and Samelson, 1997). c-Cbl that a common E2 motif is recognized by the two E3 recognizes activated RTKs and the ZAP-70/Syk kinases families. The structure reveals a rigid coupling beby binding a phosphotyrosine sequence motif through tween the peptide binding and the E2 binding domains its SH2-containing tyrosine kinase binding (TKB) doand a conserved surface channel leading from the main, and it binds an E2 through its conserved RING peptide to the E2 active site, suggesting that RING domain (Joazeiro et al., 1999; Levkowitz et al., 1999; E3s may function as scaffolds that position the sub-Yokouchi et al., 1999). The RING domain has a central strate and the E2 optimally for ubiquitin transfer. role in c-Cbl function, because its deletion or disruption, as observed in the murine retrovirus-encoded v-Cbl and