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.

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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 [17].

Generally, ubiquitination of targets by Cbl proteins occurs as either mono- or poly-ubiquitination [2].

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.