The c-Cbl proto-oncogene was first identified as a 120,000 Mr protein that was rapidly phosphorylated on tyrosine residues following the stimulation of a wide variety of receptors, including the T-cell receptor, the B cell receptor, the Fc receptor, the EGF receptor, the PDGF receptor, the CSF-1 receptor, as well as receptors for several cytokines (interleukin-3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, and prolactin). Cbl contains 22 tyrosine residues as well as proline-rich domain, and thus can bind to many different molecules that contain either SH2 or SH3 domains. Molecules that have been shown to bind to c-Cbl include Crk, Crk-L, Grb 2, the p85 subunit of PI 3-kinase, src-like kinases, and members of the Syk/ZAP70 family of tyrosine kinases suggesting that Cbl may function as a scaffolding molecule. Cbl may also function as a negative regulator of the ZAP70 . The recent finding that c-Cbl functions as a component of a ubiquitin ligase complex and there by mediate dow n-regulation of the EGF receptor suggests a new and interesting role of Cbl in regulating signaling events. Likewise the suggestion that Cbl may be associated with the insulin receptor in lipid rafts suggests other interesting roles for this complex molecule. Clearly Cbl is a molecule whose time has come!
