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A large body of biochemical and cell biological work [1-3,14] has led to our current paradigms that Cbl-family E3 ubiquitin ligases serve as negative regulators of PTK signaling.
The negative regulatory role of Cbl proteins indicated by biochemical and cell biological analyses has led to studies of animal models that have provided a number of novel insights into both their physiological functions and the pathological consequences of their defective expression or function.
Germline deletion of Cbl is associated with a series of mild to moderate phenotypes during development.
Among mammalian Cbl proteins, Cbl and Cbl-b contain extensive additional C-terminal regions that serve to mediate protein-protein interactions.
These include a proline-rich region that mediates interactions of Cbl proteins with SH3 domain-containing proteins including Src-family kinases, Grb2, Cin-85 and others; several tyrosine residues whose phosphorylation generates binding motifs for interaction with SH2 domain-containing signaling proteins including Vav-family guanine nucleotide exchange factors (GEFs) for Rho-family GTPases (human Cbl Y700), p85 subunit of PI 3-kinase (human Cbl Y731) and Crkfamily adaptor proteins that link Cbl proteins to C3G, a GEF for Rasrelated small GTPase Rap1 (human Cbl Y774).
In contrast to individual knockouts, germ line deletion of Cbl and Cbl-b together leads to early embryonic lethality, indicating their redundant but essential functions during embryogenesis.
Importantly, use of a conditional (floxed) allele of Cbl on a Cbl-b-null background has allowed for tissue-selective deletion of Cbl and Cbl-b, demonstrating that these two proteins function redundantly to regulate key physiological functions.
It is clear that proteins that are in complex with activated PTK-associated Cbl proteins also undergo ubiquitination .
Generally, ubiquitination of targets by Cbl proteins occurs as either mono- or poly-ubiquitination .
The TKB domain is followed by a highly conserved linker helical region (LHR) and a RING (Really Interesting New Gene) finger domain; these two regions together form the structural platform for binding to an ubiquitin conjugating enzyme (E2) and this interaction is essential for E3 ligase activity of Cbl proteins.
The three N-terminal domains (TKB, linker and RING finger) are necessary as well as sufficient for activated tyrosine kinase-directed E3 ligase activity [8,9].
Structure and domains of Cbl proteins from various indicated species are shown.