Beyond the RING: CBL proteins as multivalent adapters

Following discovery of c-Cbl, a cellular form of the transforming retrovira l protein v-Cbl, multiple Cbl-related proteins have been identified in vert ebrate and invertebrate organisms. c-Cbl and its homologues are capable of interacting with numerous proteins involved in cell signaling, including va rious molecular adapters and protein tyrosine kinases. It appears that Cbl proteins play several functional roles, acting both as multivalent adapters and inhibitors of various protein tyrosine kinases. The latter function is linked, to a substantial extent, to the E3 ubiquitin-ligase activity of Cb l proteins. Experimental evidence for these functions, interrelations betwe en them, and their biological significance are addressed in this review, wi th the main accent placed on the adapter functions of Cbl proteins.