2d9s

Structural highlights

Disease

CBL_MOUSE Note=Can be converted to an oncogenic protein by deletions or mutations that disturb its ability to down-regulate RTKs.

Function

CBL_MOUSE Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The Tyr-737 phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function.^{[1] [2] [3] [4] [5]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Ubiquitin protein ligase 3D structures

References

1. ↑ Miyake S, Lupher ML Jr, Druker B, Band H. The tyrosine kinase regulator Cbl enhances the ubiquitination and degradation of the platelet-derived growth factor receptor alpha. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7927-32. PMID:9653117
2. ↑ Lee PS, Wang Y, Dominguez MG, Yeung YG, Murphy MA, Bowtell DD, Stanley ER. The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation. EMBO J. 1999 Jul 1;18(13):3616-28. PMID:10393178 doi:10.1093/emboj/18.13.3616
3. ↑ Duval M, Bedard-Goulet S, Delisle C, Gratton JP. Vascular endothelial growth factor-dependent down-regulation of Flk-1/KDR involves Cbl-mediated ubiquitination. Consequences on nitric oxide production from endothelial cells. J Biol Chem. 2003 May 30;278(22):20091-7. Epub 2003 Mar 19. PMID:12649282 doi:10.1074/jbc.M301410200
4. ↑ Sun J, Pedersen M, Ronnstrand L. The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction. J Biol Chem. 2009 Apr 24;284(17):11039-47. doi: 10.1074/jbc.M808058200. Epub 2009, Mar 5. PMID:19265199 doi:10.1074/jbc.M808058200
5. ↑ Kim J, Lee H, Kim Y, Yoo S, Park E, Park S. The SAM domains of Anks family proteins are critically involved in modulating the degradation of EphA receptors. Mol Cell Biol. 2010 Apr;30(7):1582-92. doi: 10.1128/MCB.01605-09. Epub 2010 Jan, 25. PMID:20100865 doi:10.1128/MCB.01605-09