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Gene Review

Cbl  -  Casitas B-lineage lymphoma

Mus musculus

Synonyms: 4732447J05Rik, Casitas B-lineage lymphoma proto-oncogene, Cbl-2, E3 ubiquitin-protein ligase CBL, Proto-oncogene c-Cbl, ...
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Disease relevance of Cbl


High impact information on Cbl

  • This inhibits the binding of Cbl by the EGF receptor and thus prevents Cbl from catalyzing receptor ubiquitination [6].
  • Here, we show that activation of Cdc42 protects the EGF receptor from the negative regulatory activity of the c-Cbl ubiquitin ligase [6].
  • This process is independent of PI(3)K, but requires the translocation of Cbl, Crk and C3G to the lipid raft [7].
  • We previously described a pathway involving the insulin-stimulated tyrosine phosphorylation of Cbl, which is recruited to the insulin receptor by the adapter protein CAP [7].
  • One such substrate is the Cbl proto-oncogene product [8].

Chemical compound and disease context of Cbl

  • These genetic and biochemical data clearly demonstrate that Src-family tyrosine kinases serve as a critical signal relay, via phosphorylation of c-Cbl, for fat accumulation, and provide potential new strategies for treating obesity [9].

Biological context of Cbl


Anatomical context of Cbl


Associations of Cbl with chemical compounds

  • APS is a Cbl-binding protein that is tyrosine phosphorylated by the insulin receptor kinase [10].
  • The binding of the fusion proteins to Cbl occurred regardless of whether Cbl was tyrosine-phosphorylated or not, and the binding could not be disrupted by the addition of 30 mM free phosphotyrosine [16].
  • However, siRNA-mediated gene silencing of both Cbl isoforms or CAP or CrkII in these cells failed to attenuate insulin-stimulated deoxyglucose transport or Myc-tagged GLUT4-GFP translocation at either sub-maximal or maximal concentrations of insulin [17].
  • Cbl proteins formed homo- and heterodimers in vivo, which required the participation of a conserved leucine zipper domain [18].
  • Binding of the Fyn SH2 domain to Cbl was not disrupted by the addition of phosphotyrosine, phosphoserine, or phosphothreonine [12].

Physical interactions of Cbl

  • These data suggest the unexpected conclusion that the Fyn SH2 domain may bind to Cbl in a phosphotyrosine-independent manner [16].
  • The c-cbl protooncogene product (c-Cbl) is a 120-kDa protein that has been shown to bind to the Src homology 3 domains of various proteins, suggesting its involvement in signal transduction pathways [19].
  • This study identifies a step involving ZAP-70/cbl interaction that is critical for rapid internalization of the TCR/CD3 complex at the CD8 T cell/APC synapse [20].
  • Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells [21].
  • The Crkl SH2 domain binds specifically to Cbl [22].

Enzymatic interactions of Cbl

  • 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 vesicular structures [4].
  • The Fyn SH2 domain bound to both tyrosine-phosphorylated and nonphosphorylated Cbl, implying that this interaction might be phosphotyrosine-independent [12].
  • In contrast, immunoprecipitated JAK2 was not able to phosphorylate this same region of Cbl [12].
  • Crkl is complexed with tyrosine-phosphorylated Cbl in Ph-positive leukemia [22].
  • After stimulation of the T cell receptor (TCR), the tyrosine residues 292 and 315 in interdomain B of the protein tyrosine kinase ZAP-70 become phosphorylated and plausibly function as docking sites for Cbl and Vav1, respectively [23].

Co-localisations of Cbl

  • By immunofluorescence microscopy we have determined that c-Cbl co-localizes with the adaptor protein Crk to submembranous actin lamellae in NIH 3T3 fibroblasts and that c-Cbl's actin localization requires specific SH3-binding sequences [24].

Regulatory relationships of Cbl

  • DNA synthesis initiated by constitutively activated Src was also blocked by Cbl expression, but curiously by the G306E mutant as well [25].
  • However, M-CSF induces tyrosine phosphorylation of c-Cbl, but not p130Cas in pOCs in suspension, confirming the role of c-Cbl as a downstream effector of c-Fms [26].
  • Second, Cbl-deficient thymocytes expressed CD3 and CD4 molecules at higher levels, which consequently may increase the avidity of TCR/major histocompatibility complex/coreceptor interaction [27].
  • These results support a model in which Syk can initiate and directly activate the T cell's signaling machinery and position Cbl as a primary tyrosine kinase substrate in this pathway [28].
  • First, Cbl deficiency markedly up-regulated the activity of ZAP-70 and mitogen-activated protein kinases [27].

Other interactions of Cbl

  • c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption [4].
  • We propose that c-Cbl plays a regulatory role in glycoprotein VI (GPVI)/Fc receptor gamma (FcRgamma)-chain-dependent platelet activation through its interaction with Syk [29].
  • How c-Cbl interacts with proteins, such as Grb2, phosphatidylinositol 3-kinase, and phosphorylated receptors, is well understood, but its role in these complexes is unclear [5].
  • The constitutive association of Cbl with Fyn was also observed [16].
  • These data are consistent with the hypothesis that CAP, Cbl iso-forms, and CrkII are not required components of insulin signaling to GLUT4 transporters [17].

Analytical, diagnostic and therapeutic context of Cbl

  • The addition of [gamma-32P]ATP to either anti-Cbl immunoprecipitates or anti-Fyn immunoprecipitates resulted in the phosphorylation of both Cbl and Fyn as demonstrated by immunoprecipitation of the phosphorylated proteins with specific antisera [12].
  • Microinjection of two different affinity purified polyclonal antisera against Cbl boosted a suboptimal PDGF-stimulated mitogenic response [25].
  • Examination of cells by immunofluorescence revealed that c-Cbl is diffusely distributed in the cytoplasm in both unstimulated macrophages and EGF receptor-overexpressing cells and translocated to a more specific compartment of the cell, consistent with the trans-Golgi region, following Fc gamma R clustering and EGF stimulation, respectively [19].
  • The results provide a paradigm for studies of the mechanisms underlying Cbl attenuation of proliferative responses induced by ligation of receptor tyrosine kinases [30].
  • Transplantation experiments showed that the mammary stroma was responsible for the increased side branching observed in Cbl-null mice [31].


  1. p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinases, Grb2 and Shc adaptors, and the p85 subunit of phosphatidylinositol 3-kinase. Panchamoorthy, G., Fukazawa, T., Miyake, S., Soltoff, S., Reedquist, K., Druker, B., Shoelson, S., Cantley, L., Band, H. J. Biol. Chem. (1996) [Pubmed]
  2. Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl. Thien, C.B., Langdon, W.Y. Oncogene (1997) [Pubmed]
  3. Isolation and characterization of a novel, transforming allele of the c-Cbl proto-oncogene from a murine macrophage cell line. Bisson, S.A., Ujack, E.E., Robbins, S.M. Oncogene (2002) [Pubmed]
  4. c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption. Tanaka, S., Amling, M., Neff, L., Peyman, A., Uhlmann, E., Levy, J.B., Baron, R. Nature (1996) [Pubmed]
  5. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Murphy, M.A., Schnall, R.G., Venter, D.J., Barnett, L., Bertoncello, I., Thien, C.B., Langdon, W.Y., Bowtell, D.D. Mol. Cell. Biol. (1998) [Pubmed]
  6. Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation. Wu, W.J., Tu, S., Cerione, R.A. Cell (2003) [Pubmed]
  7. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Chiang, S.H., Baumann, C.A., Kanzaki, M., Thurmond, D.C., Watson, R.T., Neudauer, C.L., Macara, I.G., Pessin, J.E., Saltiel, A.R. Nature (2001) [Pubmed]
  8. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Baumann, C.A., Ribon, V., Kanzaki, M., Thurmond, D.C., Mora, S., Shigematsu, S., Bickel, P.E., Pessin, J.E., Saltiel, A.R. Nature (2000) [Pubmed]
  9. Requirement of SRC-family tyrosine kinases in fat accumulation. Sun, Y., Ma, Y.C., Huang, J., Chen, K.Y., McGarrigle, D.K., Huang, X.Y. Biochemistry (2005) [Pubmed]
  10. APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Liu, J., Kimura, A., Baumann, C.A., Saltiel, A.R. Mol. Cell. Biol. (2002) [Pubmed]
  11. The proto-oncogene product p120(cbl) links c-Src and phosphatidylinositol 3'-kinase to the integrin signaling pathway. Ojaniemi, M., Martin, S.S., Dolfi, F., Olefsky, J.M., Vuori, K. J. Biol. Chem. (1997) [Pubmed]
  12. Fyn associates with Cbl and phosphorylates tyrosine 731 in Cbl, a binding site for phosphatidylinositol 3-kinase. Hunter, S., Burton, E.A., Wu, S.C., Anderson, S.M. J. Biol. Chem. (1999) [Pubmed]
  13. Impaired plasma membrane targeting of Grb2-murine son of sevenless (mSOS) complex and differential activation of the Fyn-T cell receptor (TCR)-zeta-Cbl pathway mediate T cell hyporesponsiveness in autoimmune nonobese diabetic mice. Salojin, K., Zhang, J., Cameron, M., Gill, B., Arreaza, G., Ochi, A., Delovitch, T.L. J. Exp. Med. (1997) [Pubmed]
  14. Src kinase activity is essential for osteoclast function. Miyazaki, T., Sanjay, A., Neff, L., Tanaka, S., Horne, W.C., Baron, R. J. Biol. Chem. (2004) [Pubmed]
  15. Dynamin forms a Src kinase-sensitive complex with Cbl and regulates podosomes and osteoclast activity. Bruzzaniti, A., Neff, L., Sanjay, A., Horne, W.C., De Camilli, P., Baron, R. Mol. Biol. Cell (2005) [Pubmed]
  16. Phosphorylation of Cbl following stimulation with interleukin-3 and its association with Grb2, Fyn, and phosphatidylinositol 3-kinase. Anderson, S.M., Burton, E.A., Koch, B.L. J. Biol. Chem. (1997) [Pubmed]
  17. RNAi-based analysis of CAP, Cbl, and CrkII function in the regulation of GLUT4 by insulin. Mitra, P., Zheng, X., Czech, M.P. J. Biol. Chem. (2004) [Pubmed]
  18. The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport. Liu, J., DeYoung, S.M., Hwang, J.B., O'Leary, E.E., Saltiel, A.R. J. Biol. Chem. (2003) [Pubmed]
  19. Tyrosine phosphorylation and translocation of the c-cbl protein after activation of tyrosine kinase signaling pathways. Tanaka, S., Neff, L., Baron, R., Levy, J.B. J. Biol. Chem. (1995) [Pubmed]
  20. Selective defect in antigen-induced TCR internalization at the immune synapse of CD8 T cells bearing the ZAP-70(Y292F) mutation. Davanture, S., Leignadier, J., Milani, P., Soubeyran, P., Malissen, B., Malissen, M., Schmitt-Verhulst, A.M., Boyer, C. J. Immunol. (2005) [Pubmed]
  21. Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells. Marengère, L.E., Mirtsos, C., Kozieradzki, I., Veillette, A., Mak, T.W., Penninger, J.M. J. Immunol. (1997) [Pubmed]
  22. Crkl is complexed with tyrosine-phosphorylated Cbl in Ph-positive leukemia. de Jong, R., ten Hoeve, J., Heisterkamp, N., Groffen, J. J. Biol. Chem. (1995) [Pubmed]
  23. T cell development and T cell responses in mice with mutations affecting tyrosines 292 or 315 of the ZAP-70 protein tyrosine kinase. Magnan, A., Di Bartolo, V., Mura, A.M., Boyer, C., Richelme, M., Lin, Y.L., Roure, A., Gillet, A., Arrieumerlou, C., Acuto, O., Malissen, B., Malissen, M. J. Exp. Med. (2001) [Pubmed]
  24. c-Cbl localizes to actin lamellae and regulates lamellipodia formation and cell morphology. Scaife, R.M., Langdon, W.Y. J. Cell. Sci. (2000) [Pubmed]
  25. The proto-oncogene c-Cbl is a negative regulator of DNA synthesis initiated by both receptor and cytoplasmic tyrosine kinases. Broome, M.A., Galisteo, M.L., Schlessinger, J., Courtneidge, S.A. Oncogene (1999) [Pubmed]
  26. Distinct roles of p130Cas and c-Cbl in adhesion-induced or macrophage colony-stimulating factor-mediated signaling pathways in prefusion osteoclasts. Nakamura, I., Rodan, G.A., Duong, l.e. .T. Endocrinology (2003) [Pubmed]
  27. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Naramura, M., Kole, H.K., Hu, R.J., Gu, H. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  28. Direct T cell activation by chimeric single chain Fv-Syk promotes Syk-Cbl association and Cbl phosphorylation. Fitzer-Attas, C.J., Schindler, D.G., Waks, T., Eshhar, Z. J. Biol. Chem. (1997) [Pubmed]
  29. Rapid ubiquitination of Syk following GPVI activation in platelets. Dangelmaier, C.A., Quinter, P.G., Jin, J., Tsygankov, A.Y., Kunapuli, S.P., Daniel, J.L. Blood (2005) [Pubmed]
  30. The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation. Lee, P.S., Wang, Y., Dominguez, M.G., Yeung, Y.G., Murphy, M.A., Bowtell, D.D., Stanley, E.R. EMBO J. (1999) [Pubmed]
  31. TGF-beta, c-Cbl, and PDGFR-alpha the in mammary stroma. Crowley, M.R., Bowtell, D., Serra, R. Dev. Biol. (2005) [Pubmed]
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