High impact information on Cbl

• In addition, Egfr activity has to be repressed through the activity of D-cbl to ensure the absence of signaling in the ventral most follicle cells [1].
• In lysates of adult transgenic Drosophila melanogaster, GST-DCbl binds to the tyrosine-phosphorylated 150-kDa torso-DER chimeric receptor [2].
• Expression of D-Cbl directed by the sevenless enhancer in intact Drosophila compromises severely the development of the R7 photoreceptor neuron [2].
• Interactions of Drosophila Cbl with epidermal growth factor receptors and role of Cbl in R7 photoreceptor cell development [2].
• Evidence for direct interaction between Sprouty and Cbl [3].

Biological context of Cbl

• Here we report biochemical and genetic characterization of the Drosophila homologue of c-Cbl, a negative regulator of signal transduction with ubiquitin-protein ligase activity [4].
• In addition, our data show genetic and biochemical links between D-Cbl and proteins involved in endocytosis and ubiquitination, suggesting that v-Cbl may exert its oncogenic effect by enhancing receptor signalling as a consequence of suppressing receptor endocytosis [4].
• D-Cbl, the Drosophila homologue of the c-Cbl proto-oncogene, interacts with the Drosophila EGF receptor in vivo, despite lacking C-terminal adaptor binding sites [5].
• The Cbl family of proteins act as E3 ubiquitin-protein ligases and have been associated with the down regulation of a variety of receptor tyrosine kinases [6].
• D-cbl, a negative regulator of the Egfr pathway, is required for dorsoventral patterning in Drosophila oogenesis [1].

Anatomical context of Cbl

• Cbl protein is shown to be localised to axons of the longitudinal connectives and commissures in the central nervous system [6].
• Finally, oncogenic mutants of Cbl, when expressed in fibroblasts, upregulate the signaling cascade downstream of the platelet-derived growth factor receptor alpha in a Cbl-PTB domain-dependent manner [7].
• Both isoforms are maternally expressed but the long isoform of D-cbl is also transiently expressed in the invaginating mesoderm and later is specifically expressed in neurons of the central nervous system (CNS) [6].

Associations of Cbl with chemical compounds

• Cbl has emerged as a novel signal transducing protein downstream of a number of cell surface receptors coupled to tyrosine kinases [7].
• There is high conservation between Cbl species in the amino-terminal region that contains a putative phosphotyrosine binding domain and a Ring finger motif [8].
• Cbl and Sprint both regulate early steps of RTK endocytosis [9].

Regulatory relationships of Cbl

• The Cbl family of proteins downregulate epidermal growth factor receptor (Egfr) signaling via receptor internalization and destruction [10].

Other interactions of Cbl

• The corresponding mutation in human Cbl inactivates the PTB domain function and abrogates Cbl-mediated regulation of tyrosine kinase function [11].
• Cbl proteins associate with many different cell signalling molecules suggesting that they may have functions outside of the RING finger-mediated ubiquitin ligase activity [6].
• Additionally, both Caenorhabditis elegans and Drosophila Cbl homologs, SLI-1 and D-Cbl, respectively, have been identified as negative regulators of the LET-23/DER receptor tyrosine kinases [7].

References