Cbl protein

Tanaka, S., L. Neff, R. Baron, and J. B. Levy. Tyrosine phosphorylation and translocation of the c-Cbl protein after activation of tyrosine kinase signaling pathways. J Biol Chem. 270 14347-14351.1995. 

Before discussing the mechanism of the conformational trigger, it is informative to review other data on Cbl-protein contacts. The role of the dmbim axial base... 

The Cbl proteins are single-subunit E3 ubiquitin ligases that are involved in the down-regulation of transmembrane receptors. They interact with phosphotyrosine residues on activated receptor tyrosine kinases via a specific SH2 domain (see Section8.2.1),... 

The signaling molecules that are downregulated by the Cbl proteins include receptor tyrosine kinases like the epidermal growth factor receptor (EGFR, see Chapter 8) and nonreceptor tyrosine kinases like Zap 70 (see Section 11.3). The central importance of the Cbl proteins for cellular regulation is highlighted by the observation that oncogenic forms of Cbl have been found in mouse retroviruses. 

Fujita Y, Krause G, Scheffner M et al (2002) Hakai, a c-Cbl-like protein, ubiquitinates and induces endo-cytosis of the E-cadherin complex. Nat Cell Biol 4(3) 222-231... 

Among the substrates of Src are other nonreceptor PTKs (e.g., Fak, Syk, and Tec kinases), RTKs (e.g. EGF and PDGF receptors), phospholipase Cy, PI3-kinase, phosphatases (e.g., SHP-2 and PP2A), and adaptor (e.g., She and Cbl) as well as focal adhesion proteins (e.g., paxillin, pl30Cas andtensin). Src-mediated phosphorylation either modulates enzymatic activity of... 

Thomas Cbl is a ring finger protein which is involved in down-regulation of the receptor. This didn t fall out of the original screen. Are there mutants in Cbl as well ... 

Swaminathan, G., and A. Y. Tsygankov. 2006. The Cbl family proteins Ring leaders in regulation of cell signaling. J Cell Physiol 209(1) 21 13. 

In addition to containing protein-protein interaction motifs, E3-substrate specificity may be affected by post-translational modifications. In particular, phosphorylation can alter E3-substrate interactions. One example is p53 where certain phosphorylations inhibit its direct binding to Mdm2, while others indirectly enhance their association by promoting nuclear localization of p53 [104-106]. Phosphorylation also directly enhances substrate interactions, as exemplified by the Cbls, which include phospho-tyrosine binding domains (see below) [107]. 

Families of RING finger proteins play important roles in cell regulation, signal transduction and apoptosis. Some of the more prominent families are the Siahs, lAPs, TRAFs, and Cbls (Figure 4.4). Short summaries of these are presented below. 

Zheng, N., et al.. Structure of a c-Cbl-UbcH7 complex RING domain function in ubiquitin-protein ligases. Cell, 2000, 102(4), 533-9. 

JoAZEiRO, C. A., et al.. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science, 1999,... 

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