| Structural highlights
Disease
[CBL_HUMAN] Defects in CBL are the cause of Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:613563]. A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects.[1]
Function
[KSYK_HUMAN] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.[2] [3] [4] [5] [6] [7] [CBL_HUMAN] 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-731 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.[8] [9] [10] [11] [12] [13] [14] [15]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The c-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins. An obligatory, intrapeptidyl H-bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orients the peptide into a positively charged pocket on c-Cbl. Surprisingly, c-Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H-bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c-Cbl; this may enable the selective sequestration of c-Cbl from other target proteins.
Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.,Ng C, Jackson RA, Buschdorf JP, Sun Q, Guy GR, Sivaraman J EMBO J. 2008 Mar 5;27(5):804-16. Epub 2008 Feb 14. PMID:18273061[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010 Aug 13;87(2):250-7. doi: 10.1016/j.ajhg.2010.06.015. Epub, 2010 Jul 8. PMID:20619386 doi:10.1016/j.ajhg.2010.06.015
- ↑ Law CL, Chandran KA, Sidorenko SP, Clark EA. Phospholipase C-gamma1 interacts with conserved phosphotyrosyl residues in the linker region of Syk and is a substrate for Syk. Mol Cell Biol. 1996 Apr;16(4):1305-15. PMID:8657103
- ↑ Deckert M, Elly C, Altman A, Liu YC. Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases. J Biol Chem. 1998 Apr 10;273(15):8867-74. PMID:9535867
- ↑ Chiu CW, Dalton M, Ishiai M, Kurosaki T, Chan AC. BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins. EMBO J. 2002 Dec 2;21(23):6461-72. PMID:12456653
- ↑ Urzainqui A, Serrador JM, Viedma F, Yanez-Mo M, Rodriguez A, Corbi AL, Alonso-Lebrero JL, Luque A, Deckert M, Vazquez J, Sanchez-Madrid F. ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1. Immunity. 2002 Oct;17(4):401-12. PMID:12387735
- ↑ Shim EK, Moon CS, Lee GY, Ha YJ, Chae SK, Lee JR. Association of the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) with the p85 subunit of phosphoinositide 3-kinase. FEBS Lett. 2004 Sep 24;575(1-3):35-40. PMID:15388330 doi:10.1016/j.febslet.2004.07.090
- ↑ Cholay M, Reverdy C, Benarous R, Colland F, Daviet L. Functional interaction between the ubiquitin-specific protease 25 and the SYK tyrosine kinase. Exp Cell Res. 2010 Feb 15;316(4):667-75. doi: 10.1016/j.yexcr.2009.10.023. Epub, 2009 Nov 10. PMID:19909739 doi:10.1016/j.yexcr.2009.10.023
- ↑ Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science. 1999 Oct 8;286(5438):309-12. PMID:10514377
- ↑ Howlett CJ, Robbins SM. Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation. Oncogene. 2002 Mar 7;21(11):1707-16. PMID:11896602 doi:10.1038/sj.onc.1205228
- ↑ Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne WC, Baron R. Src kinase activity is essential for osteoclast function. J Biol Chem. 2004 Apr 23;279(17):17660-6. Epub 2004 Jan 22. PMID:14739300 doi:10.1074/jbc.M311032200
- ↑ Kaabeche K, Lemonnier J, Le Mee S, Caverzasio J, Marie PJ. Cbl-mediated degradation of Lyn and Fyn induced by constitutive fibroblast growth factor receptor-2 activation supports osteoblast differentiation. J Biol Chem. 2004 Aug 27;279(35):36259-67. Epub 2004 Jun 9. PMID:15190072 doi:10.1074/jbc.M402469200
- ↑ Bonaventure J, Horne WC, Baron R. The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor. FEBS J. 2007 Jun;274(12):3078-93. Epub 2007 May 17. PMID:17509076 doi:10.1111/j.1742-4658.2007.05835.x
- ↑ Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ. FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival. Bone. 2008 Jun;42(6):1032-9. doi: 10.1016/j.bone.2008.02.009. Epub 2008 Feb 29. PMID:18374639 doi:10.1016/j.bone.2008.02.009
- ↑ Wehrle C, Van Slyke P, Dumont DJ. Angiopoietin-1-induced ubiquitylation of Tie2 by c-Cbl is required for internalization and degradation. Biochem J. 2009 Oct 12;423(3):375-80. doi: 10.1042/BJ20091010. PMID:19689429 doi:10.1042/BJ20091010
- ↑ Severe N, Miraoui H, Marie PJ. The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination. J Biol Chem. 2011 Jul 8;286(27):24443-50. doi: 10.1074/jbc.M110.197525. Epub 2011, May 19. PMID:21596750 doi:10.1074/jbc.M110.197525
- ↑ Ng C, Jackson RA, Buschdorf JP, Sun Q, Guy GR, Sivaraman J. Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates. EMBO J. 2008 Mar 5;27(5):804-16. Epub 2008 Feb 14. PMID:18273061 doi:10.1038/emboj.2008.18
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