Pathway
Regulation of signaling by CBL
Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation. Cbl negatively regulates PI3K via this mechanism. The binding of Cbl to the p85 subunit of PI3K is mediated at least in part by tyrosine phosphorylation at Y731. Fyn and the related kinases Hck and Lyn are known to be associated with Cbl. Fyn is proven capable of Cbl Y731 phosphorylation.The association of Fyn and Cbl has been described as constitutive. CBL further associates with the p85 subunit of PI3K, this also described as constitutive and mediated by the SH3 domain of p85. Binding of the SH2 domain of p85 to a specific phosphorylation site in Cbl is postulated to explain the the increase in Cbl/p85 association seen in activated cells which negatively regulates PI3K activity. The negative effect of increased Cbl-PI3K interaction is mediated by Y731 of Cbl. Cbl binding increases PI3K ubiquitination and proteasome degradation.
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Cbl is constitutively associated with Grb in resting hematopoietic cells. Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain binds the adaptor protein CRKL. Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules. Cbl is tyrosine phosphorylated in response to many cytokines including IL-3, IL-2 and IL-4.
What the reference databases state
Statements
21 statements
21 statements · 1 reference database · Subject: Regulation of signaling by CBL · Sources: Reactome
- BLNK participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- CBL participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- CRK participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- CRKL participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- FYN participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- HCK participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- LYN participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- PIK3CA participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- PIK3CB participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- PIK3CD participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- PIK3R1 participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- PIK3R2 participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
Show the remaining 9
- PIK3R3 participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- RAPGEF1 participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- RPS27A participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- SYK participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- UBA52 participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- UBB participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- UBC participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- VAV1 participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only
- YES1 participates in Regulation of signaling by CBLProteinReactome R-HSA-912631Inferred only