Illustration of phosphorylation, ubiquitination as PTMs on a substrate, and domain structures of the Cbl protein family. (a, b) Phosphorylation versus ubiquitination as post-translational modifying mechanisms of a protein substrate. (c) Mammalian Cbl protein family domain structures. The Cbl proteins contain, from N to C terminus, a TKB domain, a linker region (L), RING finger domain (RF), Pro-rich regions, poly-Pro-Arg motif (PR) and a UBA domain. The TKB domain consists of a four-helix bundle (4H), an EF hand, and a variant Src homology region 2 (SH2) domain. Cbl-3 lacks the PR and UBA domain.