Cbl

Summary

Gene Symbol: Cbl
Description: Casitas B-lineage lymphoma
Alias: 4732447J05Rik, Cbl-2, c-Cbl, cbl, E3 ubiquitin-protein ligase CBL, RING-type E3 ubiquitin transferase CBL, casitas B-lineage lymphoma proto-oncogene, proto-oncogene c-CBL, signal transduction protein CBL
Species: mouse
Products:     Cbl

Top Publications

  1. Rathinam C, Thien C, Langdon W, Gu H, Flavell R. The E3 ubiquitin ligase c-Cbl restricts development and functions of hematopoietic stem cells. Genes Dev. 2008;22:992-7 pubmed publisher
    ..present study, we document that HSC development and functions are negatively regulated by the E3 ubiquitin ligase c-Cbl (casitas B-cell lymphoma)...
  2. Akiyama T, Bouillet P, Miyazaki T, Kadono Y, Chikuda H, Chung U, et al. Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim. EMBO J. 2003;22:6653-64 pubmed
    ..This was caused by the reduced ubiquitylation and proteasomal degradation of Bim that is mediated by c-Cbl. Although the number of OCs was increased in the skeletal tissues of bim-/- mice, the mice exhibited mild ..
  3. Chiang Y, Kole H, Brown K, Naramura M, Fukuhara S, Hu R, et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature. 2000;403:216-20 pubmed
    ..Here we show that T cells that are deficient in the adaptor molecule Cbl-b (ref...
  4. Chiang Y, Sommers C, Jordan M, Gu H, Samelson L, Koretzky G, et al. Inactivation of c-Cbl reverses neonatal lethality and T cell developmental arrest of SLP-76-deficient mice. J Exp Med. 2004;200:25-34 pubmed
    c-Cbl is an adaptor protein that negatively regulates signal transduction events involved in thymic-positive selection...
  5. Thien C, Bowtell D, Langdon W. Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and SLP-76 in c-Cbl-deficient thymocytes. J Immunol. 1999;162:7133-9 pubmed
    Recent studies indicate that c-Cbl and its oncogenic variants can modulate the activity of protein tyrosine kinases...
  6. Thien C, Scaife R, Papadimitriou J, Murphy M, Bowtell D, Langdon W. A mouse with a loss-of-function mutation in the c-Cbl TKB domain shows perturbed thymocyte signaling without enhancing the activity of the ZAP-70 tyrosine kinase. J Exp Med. 2003;197:503-13 pubmed
    The unique tyrosine kinase binding (TKB) domain of Cbl targets phosphorylated tyrosines on activated protein tyrosine kinases (PTKs); this targeting is considered essential for Cbl proteins to negatively regulate PTKs...
  7. Corsois L, Quatannens B, Dumont P, Aumercier M, Defresne M, Régnier D. Association of a new c-Cbl related protein with the very first stages of apoptosis induction. Cancer Detect Prev. 2002;26:93-104 pubmed
    This study investigates the involvement of the c-cbl proto-oncogene during the first stages of the apoptotic process...
  8. Hawash I, Kesavan K, Magee A, Geahlen R, Harrison M. The Lck SH3 domain negatively regulates localization to lipid rafts through an interaction with c-Cbl. J Biol Chem. 2002;277:5683-91 pubmed
    ..Overexpression of c-Cbl, a ligand of the Lck SH3 domain, depleted Lck from lipid rafts in Jurkat cells...
  9. Duan L, Miura Y, Dimri M, Majumder B, Dodge I, Reddi A, et al. Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis. J Biol Chem. 2003;278:28950-60 pubmed
    ..Overexpression studies have identified Cbl-mediated ubiquitinylation of EGFR as a mechanism of ligand-induced EGFR down-regulation...

More Information

Publications94

  1. Sanada M, Suzuki T, Shih L, Otsu M, Kato M, Yamazaki S, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460:904-8 pubmed publisher
    ..Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms ..
  2. Balagopalan L, Barr V, Sommers C, Barda Saad M, Goyal A, Isakowitz M, et al. c-Cbl-mediated regulation of LAT-nucleated signaling complexes. Mol Cell Biol. 2007;27:8622-36 pubmed
    ..The internalization of LAT was inhibited in cells expressing versions of the ubiquitin ligase c-Cbl mutated in the RING domain and in T cells from mice lacking c-Cbl...
  3. Rathinam C, Thien C, Flavell R, Langdon W. Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. Cancer Cell. 2010;18:341-52 pubmed publisher
    ..Here, by analyzing mice with a mutation in the RING finger domain of c-Cbl, we show that the E3 ubiquitin ligase activity of c-Cbl is required to restrict myeloid leukemia development...
  4. Taylor S, Dagger S, Thien C, Wikstrom M, Langdon W. Flt3 inhibitor AC220 is a potent therapy in a mouse model of myeloproliferative disease driven by enhanced wild-type Flt3 signaling. Blood. 2012;120:4049-57 pubmed publisher
    ..Using the c-Cbl RING finger mutant mouse as a model of a myeloproliferative disease (MPD) driven by wild-type Flt3, in the present ..
  5. Sun J, Pedersen M, Bengtsson S, Ronnstrand L. Grb2 mediates negative regulation of stem cell factor receptor/c-Kit signaling by recruitment of Cbl. Exp Cell Res. 2007;313:3935-42 pubmed
    ..Certain receptor tyrosine kinases, such as epidermal growth factor receptor, have been shown to indirectly recruit Cbl through the adapter protein Grb2, leading to receptor ubiquitination and degradation...
  6. Naramura M, Kole H, Hu R, Gu H. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Proc Natl Acad Sci U S A. 1998;95:15547-52 pubmed
    b>Cbl is the product of the protooncogene c-cbl and is involved in T cell antigen receptor (TCR)-mediated signaling. To understand the role of Cbl for immune system development and function, we generated a Cbl-deficient mouse strain...
  7. Heaney C, Kolibaba K, Bhat A, Oda T, Ohno S, Fanning S, et al. Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation. Blood. 1997;89:297-306 pubmed
    ..Thus, a direct interaction of CRKL and BCR-ABL is not required for CRKL to become tyrosine phosphorylated by BCR-ABL and suggests that CRKL function may still be required for BCR-ABL function through an indirect interaction. ..
  8. Murphy M, Schnall R, Venter D, Barnett L, Bertoncello I, Thien C, et al. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Mol Cell Biol. 1998;18:4872-82 pubmed
    The c-Cbl protein is tyrosine phosphorylated and forms complexes with a wide range of signalling partners in response to various growth factors...
  9. Miyake S, Lupher M, 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;95:7927-32 pubmed
    The Cbl protooncogene product has emerged as a negative regulator of receptor and nonreceptor tyrosine kinases...
  10. Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne W, Baron R. Src kinase activity is essential for osteoclast function. J Biol Chem. 2004;279:17660-6 pubmed
    ..Src forms a complex with Pyk2 and Cbl after adhesion-induced stimulation of alpha(V)beta(3) integrin...
  11. de Melker A, van der Horst G, Borst J. c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15. J Cell Sci. 2004;117:5001-12 pubmed
    c-Cbl associates with the activated EGF receptor before endocytosis...
  12. Ota Y, Samelson L. The product of the proto-oncogene c-cbl: a negative regulator of the Syk tyrosine kinase. Science. 1997;276:418-20 pubmed
    ..Regulation of Syk function occurred through interaction with the Cbl protein, itself a PTK substrate in this system...
  13. Miura Shimura Y, Duan L, Rao N, Reddi A, Shimura H, Rottapel R, et al. Cbl-mediated ubiquitinylation and negative regulation of Vav. J Biol Chem. 2003;278:38495-504 pubmed
    The Cbl ubiquitin ligase has emerged as a negative regulator of receptor and non-receptor tyrosine kinases...
  14. Thien C, Blystad F, Zhan Y, Lew A, Voigt V, Andoniou C, et al. Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion. EMBO J. 2005;24:3807-19 pubmed
    ..from the T-cell receptor (TCR) in thymocytes is negatively regulated by the RING finger-type ubiquitin ligase c-Cbl. To further investigate this regulation, we generated mice with a loss-of-function mutation in the c-Cbl RING ..
  15. Naramura M, Jang I, Kole H, Huang F, Haines D, Gu H. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat Immunol. 2002;3:1192-9 pubmed
    How Cbl family proteins regulate T cell responses is unclear...
  16. Myers M, Sosinowski T, Dragone L, White C, Band H, Gu H, et al. Src-like adaptor protein regulates TCR expression on thymocytes by linking the ubiquitin ligase c-Cbl to the TCR complex. Nat Immunol. 2006;7:57-66 pubmed
    The adaptor molecule SLAP and E3 ubiquitin ligase c-Cbl each regulate expression of T cell receptor (TCR)-CD3 on thymocytes. Here we provide genetic and biochemical evidence that both molecules function in the same pathway...
  17. Chiang Y, Jordan M, Horai R, Schwartzberg P, Koretzky G, Hodes R. Cbl enforces an SLP76-dependent signaling pathway for T cell differentiation. J Biol Chem. 2009;284:4429-38 pubmed publisher
    ..Recently, however, it has been reported that inactivation of Cbl, a ubiquitin-protein isopeptide ligase, partially rescues T cell development in SLP76-deficient mice...
  18. Mohapatra B, Zutshi N, An W, Goetz B, Arya P, Bielecki T, et al. An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. Development. 2017;144:1072-1086 pubmed publisher
    The ubiquitin ligases CBL and CBL-B are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown...
  19. Bernatchez P, Acevedo L, Fernandez Hernando C, Murata T, Chalouni C, Kim J, et al. Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function. J Biol Chem. 2007;282:30745-53 pubmed
    ..Mechanistically, myoferlin forms a complex with dynamin-2 and VEGFR-2, which prevents CBL-dependent VEGFR-2 polyubiquitination and proteasomal degradation...
  20. Niederberger N, Holmberg K, Alam S, Sakati W, Naramura M, Gu H, et al. Allelic exclusion of the TCR alpha-chain is an active process requiring TCR-mediated signaling and c-Cbl. J Immunol. 2003;170:4557-63 pubmed
    ..Loss of the ubiquitin ligase/TCR signaling adapter molecule c-Cbl, which is important in TCR down-modulation and is a negative regulator of T cell signaling, leads to increased dual ..
  21. Round J, Tomassian T, Zhang M, Patel V, Schoenberger S, Miceli M. Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells. J Exp Med. 2005;201:419-30 pubmed
    ..These findings highlight common molecular strategies used to regulate cell polarity, synapse assembly, and transducer organization in diverse cellular systems. ..
  22. Demydenko D. c-Cbl mediated ubiquitylation and regulation of cell surface exposure of CD5. Biochem Biophys Res Commun. 2010;392:500-4 pubmed publisher
    ..c-Cbl role in the process is thought to be initial ubiquitylation of the receptors targeted for degradation and assembly ..
  23. Sanger J, Wang J, Gleason L, Chowrashi P, Dube D, Mittal B, et al. Arg/Abl-binding protein, a Z-body and Z-band protein, binds sarcomeric, costameric, and signaling molecules. Cytoskeleton (Hoboken). 2010;67:808-23 pubmed publisher
    ..ArgBP2 is a member of a small family of proteins that also includes vinexin and CAP (c-Cbl-associated protein), all characterized by having one sorbin homology (SOHO) domain and three C-terminal SH3 domains...
  24. Jansen S, Sleumer L, Damen E, Meijer I, van Zoelen E, van Leeuwen J. ErbB2 and ErbB4 Cbl binding sites can functionally replace the ErbB1 Cbl binding site. Cell Signal. 2009;21:810-8 pubmed
    ..that poor downregulation of ErbB-2, -3 and -4 receptors when compared to ErbB1 is due to decreased recruitment of Cbl E3 ligase proteins...
  25. Faccio R, Takeshita S, Colaianni G, Chappel J, Zallone A, Teitelbaum S, et al. M-CSF regulates the cytoskeleton via recruitment of a multimeric signaling complex to c-Fms Tyr-559/697/721. J Biol Chem. 2007;282:18991-9 pubmed
    ..c-Cbl.PI3K complex and the downstream activation of Vav3 and Rac, two key mediators of actin remodeling...
  26. Reddi A, Ying G, Duan L, Chen G, Dimri M, Douillard P, et al. Binding of Cbl to a phospholipase Cgamma1-docking site on platelet-derived growth factor receptor beta provides a dual mechanism of negative regulation. J Biol Chem. 2007;282:29336-47 pubmed
    ..Our previous studies have established Cbl as an E3 ubiquitin ligase for ubiquitinylation and degradation of platelet-derived growth factor receptor (PDGFR) ..
  27. Morris V, Rao T, Kozak C, Gray D, Lee Chan E, Cornell T, et al. Characterization of Int-5, a locus associated with early events in mammary carcinogenesis. Oncogene Res. 1991;6:53-63 pubmed
    ..3 and 4.0 Kb. These data are consistent with the hypothesis that Int-5 contains an oncogene, different from any other previously described, involved in early events in some models of chemical carcinogenesis. ..
  28. Ribon V, Saltiel A. Insulin stimulates tyrosine phosphorylation of the proto-oncogene product of c-Cbl in 3T3-L1 adipocytes. Biochem J. 1997;324 ( Pt 3):839-45 pubmed
    We report here that the product of the c-Cbl proto-oncogene is prominently tyrosine phosphorylated in response to insulin in 3T3-L1 adipocytes...
  29. Mamchak A, Thien C, Dagger S, Lyandres J, Jiang S, Langdon W, et al. Unaltered negative selection and Treg development of self-reactive thymocytes in TCR transgenic Fyn-deficient mice. Eur J Immunol. 2010;40:539-47 pubmed publisher
    ..We further tested the role of Fyn for the adaptor function of c-Cbl, using mice containing a point mutation in c-Cbl that abolishes its E3 ubiquitin ligase function but maintains its ..
  30. Ahn M, Katsanakis K, Bheda F, Pillay T. Primary and essential role of the adaptor protein APS for recruitment of both c-Cbl and its associated protein CAP in insulin signaling. J Biol Chem. 2004;279:21526-32 pubmed
    ..Although both APS and CAP (c-Cbl-associated protein) interact with c-Cbl during insulin signaling, the relative importance of each protein in ..
  31. Lee P, Wang Y, Dominguez M, Yeung Y, Murphy M, Bowtell D, et al. The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation. EMBO J. 1999;18:3616-28 pubmed
    Colony-stimulating factor-1 (CSF-1) activation of the CSF-1 receptor (CSF-1R) causes Cbl protooncoprotein tyrosine phosphorylation, Cbl-CSF-1R association and their simultaneous multiubiquitination at the plasma membrane...
  32. Wang L, Cao H, Lu N, Liu L, Wang B, Hu T, et al. Berberine inhibits proliferation and down-regulates epidermal growth factor receptor through activation of Cbl in colon tumor cells. PLoS ONE. 2013;8:e56666 pubmed publisher
    ..In this study, we also showed that berberine stimulated ubiquitin ligase Cbl activation and Cbl's interaction with EGFR, and EGFR ubiquitinylation and down-regulation in these two cell lines ..
  33. Dieudonné F, Severe N, Biosse Duplan M, Weng J, Su Y, Marie P. Promotion of osteoblast differentiation in mesenchymal cells through Cbl-mediated control of STAT5 activity. Stem Cells. 2013;31:1340-9 pubmed publisher
    ..In this study, we investigated the role of the E3 ubiquitin ligase c-Cbl in MSC osteoblast differentiation and identified the mechanisms involved in this effect...
  34. Das M, Scappini E, Martin N, Wong K, Dunn S, Chen Y, et al. Regulation of neuron survival through an intersectin-phosphoinositide 3'-kinase C2beta-AKT pathway. Mol Cell Biol. 2007;27:7906-17 pubmed
    ..This study represents the first demonstration that ITSN, independent of its role in endocytosis, regulates a critical cellular signaling pathway necessary for cell survival. ..
  35. Rafiq K, Kolpakov M, Seqqat R, Guo J, Guo X, Qi Z, et al. c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia. Circulation. 2014;129:2031-43 pubmed publisher
    The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and nonreceptor tyrosine kinases, resulting in their ubiquitination and downregulation...
  36. Arron J, Vologodskaia M, Wong B, Naramura M, Kim N, Gu H, et al. A positive regulatory role for Cbl family proteins in tumor necrosis factor-related activation-induced cytokine (trance) and CD40L-mediated Akt activation. J Biol Chem. 2001;276:30011-7 pubmed
    ..Here, we show that TRANCE-R and CD40 recruit TRAF6, Cbl family-scaffolding proteins, and the phospholipid kinase phosphatidylinositol 3-kinase in a ligand-dependent manner...
  37. Usui R, Shibuya M, Ishibashi S, Maru Y. Ligand-independent activation of vascular endothelial growth factor receptor 1 by low-density lipoprotein. EMBO Rep. 2007;8:1155-61 pubmed
    ..We propose that LDLR-mediated use of VEGFR1 by nLDL could be a potential therapeutic target in atherosclerotic disorders. ..
  38. Wiggins C, Band H, Cook S. c-Cbl is not required for ERK1/2-dependent degradation of BimEL. Cell Signal. 2007;19:2605-11 pubmed
    ..It has been proposed that the RING finger protein Cbl binds to Bim(EL) and serves as its E3 ubiquitin ligase...
  39. Ha Thi H, Kim H, Choi S, Kang J, Kim S, Hong S. Smad7 Modulates Epidermal Growth Factor Receptor Turnover through Sequestration of c-Cbl. Mol Cell Biol. 2015;35:2841-50 pubmed publisher
    ..ligand-induced ubiquitination and degradation of activated receptor, which is induced by the E3 ubiquitin ligase c-Cbl. The C-terminal MH2 region but not MH1 region of Smad7 is critical for interaction with c-Cbl to inhibit the ..
  40. Gustin S, Thien C, Langdon W. Cbl-b is a negative regulator of inflammatory cytokines produced by IgE-activated mast cells. J Immunol. 2006;177:5980-9 pubmed
    c-Cbl and Cbl-b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules...
  41. Purev E, Neff L, Horne W, Baron R. c-Cbl and Cbl-b act redundantly to protect osteoclasts from apoptosis and to displace HDAC6 from beta-tubulin, stabilizing microtubules and podosomes. Mol Biol Cell. 2009;20:4021-30 pubmed publisher
    c-Cbl and Cbl-b are highly conserved adaptor proteins that participate in integrin signaling, regulating cytoskeletal organization, motility, and bone resorption...
  42. Tanaka S, Amling M, Neff L, Peyman A, Uhlmann E, Levy J, et al. c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption. Nature. 1996;383:528-31 pubmed
    ..We report here that the proto-oncogene product c-Cbl is tyrosine-phosphorylated in a Src-dependent manner in osteoclasts, where the two proteins colocalize on some ..
  43. Uemura N, Salgia R, Li J, Pisick E, Sattler M, Griffin J. The BCR/ABL oncogene alters interaction of the adapter proteins CRKL and CRK with cellular proteins. Leukemia. 1997;11:376-85 pubmed
    ..In BCR/ABL-transformed cells, CRKL but not CRK II, appears to form complexes which potentially link BCR/ABL, c-ABL, C3G, and SOS to the protooncoprotein, p120CBL. ..
  44. Sekine Y, Tsuji S, Ikeda O, Sugiyma K, Oritani K, Shimoda K, et al. Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase. J Immunol. 2007;179:2397-407 pubmed
    ..degradation, proteasome inhibitors block FAK degradation, and STAP-2 recruits an endogenous E3 ubiquitin ligase, Cbl, to FAK...
  45. Bulut G, Sulahian R, Yao H, Huang L. Cbl ubiquitination of p85 is essential for Epo-induced EpoR endocytosis. Blood. 2013;122:3964-72 pubmed publisher
    ..Here we have identified a novel mechanism mediating Epo-dependent EpoR internalization. Epo induces Cbl-dependent ubiquitination of the p85 regulatory subunit of PI3K, which binds to phosphotyrosines on EpoR...
  46. Chen W, Han C, Xie B, Hu X, Yu Q, Shi L, et al. Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation. Cell. 2013;152:467-78 pubmed publisher
    ..Siglec-G-induced recruitment of SHP2 and the E3 ubiquitin ligase c-Cbl to RIG-I leads to RIG-I degradation via K48-linked ubiquitination at Lys813 by c-Cbl...
  47. Caveggion E, Continolo S, Pixley F, Stanley E, Bowtell D, Lowell C, et al. Expression and tyrosine phosphorylation of Cbl regulates macrophage chemokinetic and chemotactic movement. J Cell Physiol. 2003;195:276-89 pubmed
    ..macrophages were defective in spontaneous and chemotactic migration and tyrosine phosphorylation of the Cbl protooncoprotein was decreased in both...
  48. Doherty M, Osborne D, Browning D, Parker D, Wetzel S. Anergic CD4+ T cells form mature immunological synapses with enhanced accumulation of c-Cbl and Cbl-b. J Immunol. 2010;184:3598-608 pubmed publisher
    ..Most striking, there was specific accumulation of c-Cbl and Cbl-b to the anergic synapses...
  49. Baumann C, Ribon V, Kanzaki M, Thurmond D, Mora S, Shigematsu S, et al. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature. 2000;407:202-7 pubmed
    ..One such substrate is the Cbl proto-oncogene product...
  50. Goddard A, Yuan J, Fairbairn L, Dexter M, Borrow J, Kozak C, et al. Cloning of the murine homolog of the leukemia-associated PML gene. Mamm Genome. 1995;6:732-7 pubmed
  51. Buetow L, Tria G, Ahmed S, Hock A, Dou H, Sibbet G, et al. Casitas B-lineage lymphoma linker helix mutations found in myeloproliferative neoplasms affect conformation. BMC Biol. 2016;14:76 pubmed publisher
    Casitas B-lineage lymphoma (Cbl or c-Cbl) is a RING ubiquitin ligase that negatively regulates protein tyrosine kinase (PTK) signalling...
  52. Ruschmann J, Ho V, Antignano F, Kuroda E, Lam V, Ibaraki M, et al. Tyrosine phosphorylation of SHIP promotes its proteasomal degradation. Exp Hematol. 2010;38:392-402, 402.e1 pubmed publisher
    ..We also show, using anti-SHIP immunoprecipitates, that c-Cbl and Cbl-b are associated with SHIP and that BCR-ABL induces SHIP's polyubiquitination...
  53. Levkowitz G, Oved S, Klapper L, Harari D, Lavi S, Sela M, et al. c-Cbl is a suppressor of the neu oncogene. J Biol Chem. 2000;275:35532-9 pubmed
    ..Here we show that the oncogenic form of Neu is constitutively associated with the product of the c-cbl proto-oncogene and is part of a large complex that includes the phosphoinositide 3-kinase and Shc...
  54. El Chami N, Ikhlef F, Kaszas K, Yakoub S, Tabone E, Siddeek B, et al. Androgen-dependent apoptosis in male germ cells is regulated through the proto-oncoprotein Cbl. J Cell Biol. 2005;171:651-61 pubmed
    The proto-oncoprotein Cbl is known to control several signaling processes...
  55. Holmqvist K, Welsh M, Lu L. A role of the protein Cbl in FGF-2-induced angiogenesis in murine brain endothelial cells. Cell Signal. 2005;17:1433-8 pubmed
    The Cbl protein functions both as a multivalent adaptor and a negative regulator of receptor tyrosine kinases (RTKs), the latter by directing polyubiquitination of RTKs...
  56. Zeng S, Xu Z, Lipkowitz S, Longley J. Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl). Blood. 2005;105:226-32 pubmed
    ..Here, we show that stem cell factor (SCF), the ligand for KIT, induces the interaction between KIT and Cbl proteins and their mutual degradation...
  57. Amsen D, Kruisbeek A, Bos J, Reedquist K. Activation of the Ras-related GTPase Rap1 by thymocyte TCR engagement and during selection. Eur J Immunol. 2000;30:2832-41 pubmed
    ..We find that Rap1 and proposed regulators of Rap1 (the proto-oncogene product Cbl, Crk family adaptor proteins, and the Rap1 guanine nucleotide exchange factor C3G) are expressed at equivalent ..
  58. Sattler M, Verma S, Pride Y, Salgia R, Rohrschneider L, Griffin J. SHIP1, an SH2 domain containing polyinositol-5-phosphatase, regulates migration through two critical tyrosine residues and forms a novel signaling complex with DOK1 and CRKL. J Biol Chem. 2001;276:2451-8 pubmed
    ..Overall, these data suggest that proteins that interact with SHIP1 through Tyr(917) and Tyr(1020), such as DOK1 and SHC, are likely to be involved in the regulation of SHIP1 dependent migration. ..
  59. Kojo S, Elly C, Harada Y, Langdon W, Kronenberg M, Liu Y. Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1. Proc Natl Acad Sci U S A. 2009;106:17847-51 pubmed publisher
    ..that the decreased IFN-gamma production and failed tumor rejection observed in anergized NKT cells are rescued by Cbl-b deficiency...
  60. William B, An W, Feng D, Nadeau S, Mohapatra B, Storck M, et al. Fasudil, a clinically safe ROCK inhibitor, decreases disease burden in a Cbl/Cbl-b deficiency-driven murine model of myeloproliferative disorders. Hematology. 2016;21:218-24 pubmed publisher
    Mutations in Cbl or Cbl-b gene occur in 10% of myeloproliferative disorder (MPD) patients and are associated with poor prognosis...
  61. Langdon W. The cbl oncogene: a novel substrate of protein tyrosine kinases. Aust N Z J Med. 1995;25:859-64 pubmed
    The cbl oncogene was first identified as part of a transforming retrovirus which arose in a mouse pre-B cell lymphoma...
  62. Sigismund S, Algisi V, Nappo G, Conte A, Pascolutti R, Cuomo A, et al. Threshold-controlled ubiquitination of the EGFR directs receptor fate. EMBO J. 2013;32:2140-57 pubmed publisher
    ..The ubiquitination threshold is mechanistically determined by the cooperative recruitment of the E3 ligase Cbl, in complex with Grb2, to the EGFR...
  63. Ribon V, Printen J, Hoffman N, Kay B, Saltiel A. A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes. Mol Cell Biol. 1998;18:872-9 pubmed
    The protein product of the c-Cbl proto-oncogene is prominently tyrosine phosphorylated in response to insulin in 3T3-L1 adipocytes and not in 3T3-L1 fibroblasts...
  64. Feshchenko E, Shore S, Tsygankov A. Tyrosine phosphorylation of C-Cbl facilitates adhesion and spreading while suppressing anchorage-independent growth of V-Abl-transformed NIH3T3 fibroblasts. Oncogene. 1999;18:3703-15 pubmed
    The protooncogenic protein c-Cbl becomes tyrosine phosphorylated in normal cells in response to a variety of external stimuli, as well as in cells transformed by oncogenic protein tyrosine kinases...
  65. Bisson S, Ujack E, Robbins S. Isolation and characterization of a novel, transforming allele of the c-Cbl proto-oncogene from a murine macrophage cell line. Oncogene. 2002;21:3677-87 pubmed
    The c-Cbl proto-oncogene acts as an E3 ubiquitin ligase via its RING finger domain to negatively regulate activated cellular signal transduction pathways...
  66. Katkere B, Rosa S, Drake J. The Syk-binding ubiquitin ligase c-Cbl mediates signaling-dependent B cell receptor ubiquitination and B cell receptor-mediated antigen processing and presentation. J Biol Chem. 2012;287:16636-44 pubmed publisher
    ..Knockdown studies reveal that of the two known Syk-binding E3 ubiquitin ligases c-Cbl and Cbl-b, only c-Cbl appears to have a central role in BCR ubiquitination, trafficking to MIIC, and ubiquitin-..
  67. Song H, Zhang J, Chiang Y, Siraganian R, Hodes R. Redundancy in B cell developmental pathways: c-Cbl inactivation rescues early B cell development through a B cell linker protein-independent pathway. J Immunol. 2007;178:926-35 pubmed
    ..Another adaptor protein, c-Cbl, plays a negative regulatory role in several BCR-signaling pathways...
  68. Chiusaroli R, Sanjay A, Henriksen K, Engsig M, Horne W, Gu H, et al. Deletion of the gene encoding c-Cbl alters the ability of osteoclasts to migrate, delaying resorption and ossification of cartilage during the development of long bones. Dev Biol. 2003;261:537-47 pubmed
    ..c-Cbl lies downstream of the vitronectin receptor and forms a complex with c-Src and Pyk2 in a signaling pathway that is ..
  69. Edwin F, Patel T. A novel role of Sprouty 2 in regulating cellular apoptosis. J Biol Chem. 2008;283:3181-90 pubmed
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    ..In both circumstances, the tyrosine kinase Syk is an essential signaling intermediary. We demonstrate that Cbl negatively regulates OC function by interacting with Syk(Y317)...
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    Somatic mutations of Kit have been found in leukemias and gastrointestinal stromal tumors. The proto-oncogene c-Cbl negatively regulates Kit and Flt3 by its E3 ligase activity and acts as a scaffold...
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    ..We also observed the localization of Wnt family proteins in the apical membrane of the RPE. Our results provide genetic evidence for an involvement of the Mfrp gene expressed by RPE in the degeneration of photoreceptors. ..
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    The Cbl family of ubiquitin ligases in mammals contains three members, Cbl, Cbl-b, and Cbl-3, that are involved in down-regulation of receptor tyrosine kinases (RTKs) by mediating receptor ubiquitination and degradation...
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    ..The E3 ubiquitin ligases c-Cbl and to a lesser extent Cbl-b facilitated at least partly Lys-48-linked polyubiquitination of autophosphorylated ..
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    ..b>CBL binding was strongly enhanced in membrane-associated ITK-SYK E42K and was causative for delayed disease development...
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    ..In insulin-stimulated 3T3-L1 adipocytes, APS co-precipitated with phosphorylated c-Cbl. In CHO.T-APS cells overexpressing the insulin receptor and APS, APS co-precipitated with c-Cbl but not in CHO...
  77. Chiang J, Hodes R. Cbl enforces Vav1 dependence and a restricted pathway of T cell development. PLoS ONE. 2011;6:e18542 pubmed publisher
    ..others have indicated that the requirements for ZAP-70, LAT, and SLP-76 are partially reversed by inactivation of c-Cbl (Cbl), an E3 ubiquitin ligase that targets multiple molecules for ubiquitination and degradation...
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    ..of a PI 3-kinase-independent pathway leading to activation of the TC10 GTPase, the putative intermediates CAP, c-Cbl, Cbl-b, and CrkII were selectively depleted in 3T3-L1 adipocytes using highly efficient small interfering (si) RNAs...
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    b>Cbl family proteins, Cbl and Cbl-b, are E3 ubiquitin ligases and adaptor proteins, which play important roles in bone-resorbing osteoclasts...
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    ..Erbin inhibited EGFR ubiquitination and stabilized the EGFR protein by interacting with c-Cbl. Moreover, the PDZ domain of Erbin was critical for the interaction between Erbin and c-Cbl and EGFR ubiquitination...
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    b>CBL-family ubiquitin ligases are critical negative regulators of tyrosine kinase signaling, with a clear redundancy between CBL and CBL-B evident in the immune cell and hematopoietic stem cell studies...
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