Cbl: many adaptations to regulate protein tyrosine kinases

c-Cbl is a multidomain signalling protein that was first identified as part of an oncogenic mouse retrovirus. Other mammalian homologues (Cbl-b and Cbl-3), and Cbl proteins in Drosophila melanogaster and Caenorhabditis elegans have since been identified. Loss-of-function mutations in Cbl from C. elegans (known as SLI-1) restore signalling from a weakly active LET-23 receptor tyrosine kinase (RTK), a finding that defined Cbl proteins as negative regulators of RTKs. All Cbl proteins have a unique tyrosine-kinase-binding (TKB) domain that recognizes phosphorylated tyrosines on activated RTKs, and a RING finger domain that recruits ubiquitin-conjugating enzymes. These two domains are primarily responsible for Cbl proteins functioning as ubiquitin protein ligases that direct multi-ubiquitylation and downregulation of RTKs. c-Cbl can also target and negatively regulate non-receptor tyrosine kinases such as Syk and ZAP-70, but whether the mechanism involves E3 activity remains uncertain. Cbl proteins have additional regions that mediate binding to numerous proteins that contain Src homology region 2 and 3 (SH2 and SH3) domains and 14-3-3 proteins. These regions are associated with the formation of protein complexes at the site of activated tyrosine kinases, some of which are involved in bone resorption, glucose uptake and cell spreading. Cbl proteins can be made oncogenic by overexpressing the TKB domain alone (v-Cbl) or by deleting amino acids within an α-helix in a small domain that links the TKB domain to the RING finger. These mutations disrupt TKB domain interactions with the linker α-helix and abolish E3 activity. Loss of E3 activity alone is insufficient for transformation as not all mutations that abolish RTK multi-ubiquitylation are transforming. Transformation also requires an undefined deregulation of TKB domain function, which results in the constitutive activation of RTKs. c-Cbl- and Cbl-b-deficient mice show enhanced signalling in thymocytes and peripheral T cells, respectively. In both c-Cbl and Cbl-b mutant mice, T-cell-receptor responses are uncoupled from a requirement for co-receptor stimulation.