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Gene Review

CBL  -  Cbl proto-oncogene, E3 ubiquitin protein...

Homo sapiens

Synonyms: C-CBL, CBL2, Casitas B-lineage lymphoma proto-oncogene, E3 ubiquitin-protein ligase CBL, FRA11B, ...
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Disease relevance of CBL


Psychiatry related information on CBL

  • Learner properties and attitude towards CBL were measured using psychometric scales, and knowledge by multiple-choice questions (pre- and post-test) [6].

High impact information on CBL


Chemical compound and disease context of CBL

  • Eight monoclonal antibodies were tested directed against formalin resistant antigens (T cell biased: UCHL1, MT1; B cell biased: 4KB5, L26, Ki-B3; HLA-class II: CBL 120; activation antigens: Ber-H2; myeloid biased: Mac 387, M1) in cutaneous T (N = 29) and B (N = 10) cell lymphomas and pseudolymphomas (N = 9) [12].
  • In a systematic study to elucidate the involvement of pro- and anti-apoptotic proteins in alkylating drug resistance of tumor cells, we utilized the A2780(100) line, that was selected by repeated exposure of A2780 cell line (human ovarian carcinoma line) to chlorambucil (CBL) [13].
  • We have previously shown that systemic treatment with the somatostatin analog octreotide has marked beneficial effects on renal function in rats with liver cirrhosis induced by common bile duct ligation (CBL; Jonassen TEN, Christensen S, Sørensen AM, Marcussen N, Flyvbjerg A, Andreasen F, and Petersen JS. Hepatology 29: 1387-1395, 1999) [14].
  • The single chain Fv (scFv) directed against beta2-agonist clenbuterol (CBL) was produced by using phage display technology [15].
  • In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL), we have synthesized a new estrone D-lactam steroidal ester of CBL (ESBL) [16].

Biological context of CBL


Anatomical context of CBL


Associations of CBL with chemical compounds


Physical interactions of CBL

  • The distal C terminus of CBL (residues 671-906) binds the CRKL adapter protein [17].
  • The product of the c-cbl proto-oncogene (c-Cbl) is a 120 kDa protein harboring several docking sites for Src homology 2 (SH2) domain containing proteins and proline-rich regions that have been shown to allow its constitutive association with the SH3 domains of Grb2 [26].
  • These data suggest that one function of CRKL in normal cells might be to recruit signaling molecules such as CBL into a complex with PI3K [27].

Enzymatic interactions of CBL

  • Recently c-Cbl has been reported to be phosphorylated upon CSF-1 stimulation [26].

Other interactions of CBL

  • CBL is constitutively associated with both GRB2 and the ITAM-containing receptor subunit, Fc gammaRIgamma of Fc gammaRI, providing direct evidence that CBL functions in myeloid ITAM signaling [17].
  • CBL is the second gene at 11q23.3 found to fuse with MLL [1].
  • MLL and CBL are located between STS markers D11S939 and D11S924 [1].
  • Among the three CBL proteins described in humans, CBLC (CBL3) remains poorly studied [28].
  • We have found that CBLB, a recently characterized molecule closely related to the CBL protooncogene product, is phosphorylated on tyrosine(s) following FL treatment of JEA2 human pro-B cells and THP1 monocytic cells [29].

Analytical, diagnostic and therapeutic context of CBL

  • The results of Southern blotting in conjunction with fluorescence in situ hybridization suggest that the MLL-CBL fusion was the result of an interstitial deletion [1].
  • MATERIALS AND METHODS: The effects of RA treatment on CBL and CrkL phosphorylation, as well as on protein-protein interactions, were determined in studies involving immunoprecipitations of cell extracts with specific antibodies and Western blots [18].
  • CD38 ligation with anti-CD38 Abs caused rapid, transient, dose-dependent tyrosine phosphorylation of several proteins, including the tyrosine kinase TEC and the adaptor molecule CBL, and association of tyrosine-phosphorylated proteins with phosphatidylinositol 3-kinase p85 [30].
  • Analysis of CEA-related glycoproteins immunoprecipitated with anti-CD66 mAbs followed by immunoblotting with mAb ABL 364 showed that granulocyte LeY is attached to members of the CD66 cluster, in particular to the 160/90 kD glycoprotein recognized by anti-CD66 mAb CBL/gran 10 [31].
  • METHODS: Students from 2 universities participating in a mandatory pharmacology course were given access to a CBL programme covering cardiovascular drug therapy in a controlled randomised study (n = 167) [6].


  1. Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia. Fu, J.F., Hsu, J.J., Tang, T.C., Shih, L.Y. Genes Chromosomes Cancer (2003) [Pubmed]
  2. Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells. Sattler, M., Pride, Y.B., Quinnan, L.R., Verma, S., Malouf, N.A., Husson, H., Salgia, R., Lipkowitz, S., Griffin, J.D. Oncogene (2002) [Pubmed]
  3. A novel dileucine lysosomal-sorting-signal mediates intracellular EGF-receptor retention independently of protein ubiquitylation. Tsacoumangos, A., Tsacoumango, A., Kil, S.J., Ma, L., Sönnichsen, F.D., Carlin, C. J. Cell. Sci. (2005) [Pubmed]
  4. Formation of c-Cbl.phosphatidylinositol 3-kinase complexes on lymphocyte membranes by a p56lck-independent mechanism. Hartley, D., Corvera, S. J. Biol. Chem. (1996) [Pubmed]
  5. Relationship of the human protooncogene CBL2 on 11q23 to the t(4;11), t(11;22), and t(11;14) breakpoints. Savage, P.D., Shapiro, M., Langdon, W.Y., Geurts van Kessel, A.D., Seuanez, H.N., Akao, Y., Croce, C., Morse, H.C., Kersey, J.H. Cytogenet. Cell Genet. (1991) [Pubmed]
  6. Attitude towards computer-based learning: determinants as revealed by a controlled interventional study. Hahne, A.K., Benndorf, R., Frey, P., Herzig, S. Medical education. (2005) [Pubmed]
  7. Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Jones, C., Penny, L., Mattina, T., Yu, S., Baker, E., Voullaire, L., Langdon, W.Y., Sutherland, G.R., Richards, R.I., Tunnacliffe, A. Nature (1995) [Pubmed]
  8. Cbl: many adaptations to regulate protein tyrosine kinases. Thien, C.B., Langdon, W.Y. Nat. Rev. Mol. Cell Biol. (2001) [Pubmed]
  9. SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC. Kant, A.M., De, P., Peng, X., Yi, T., Rawlings, D.J., Kim, J.S., Durden, D.L. Blood (2002) [Pubmed]
  10. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Cohen, S., Dadi, H., Shaoul, E., Sharfe, N., Roifman, C.M. Blood (1999) [Pubmed]
  11. Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins. Barber, D.L., Mason, J.M., Fukazawa, T., Reedquist, K.A., Druker, B.J., Band, H., D'Andrea, A.D. Blood (1997) [Pubmed]
  12. Formalin-resistant leukocyte surface antigens in the diagnosis of cutaneous malignant lymphomas. Hauschild, A., Sterry, W. Am. J. Pathol. (1989) [Pubmed]
  13. Acquired alkylating drug resistance of a human ovarian carcinoma cell line is unaffected by altered levels of pro- and anti-apoptotic proteins. Roy, G., Horton, J.K., Roy, R., Denning, T., Mitra, S., Boldogh, I. Oncogene (2000) [Pubmed]
  14. Intrarenal octreotide treatment prevents sodium retention in liver cirrhotic rats: evidence for direct effects within the thick ascending limb of Henle's loop. Jonassen, T.E., Christensen, S., Marcussen, N., Petersen, J.S. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  15. Production and characterization of single chain Fv directed against beta2-agonist clenbuterol. Pan, K., Wang, H., Zhang, H.B., Liu, H.W., Lei, H.T., Huang, L., Sun, Y.M. J. Agric. Food Chem. (2006) [Pubmed]
  16. The effect of an estrone D-lactam steroid ester derivative on breast cancer cells and its predicted binding interactions with the ligand binding domain of estrogen receptor-alpha. Kontos, M., Nikolopoulou, M., Trafalis, D.T., Geromichalos, G.D., Koukoulitsa, C., Camoutsis, J.C., Bastounis, E., Karamanakos, P. Oncol. Res. (2005) [Pubmed]
  17. CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling. Park, R.K., Kyono, W.T., Liu, Y., Durden, D.L. J. Immunol. (1998) [Pubmed]
  18. All-trans-retinoic acid induces tyrosine phosphorylation of the CrkL adapter in acute promyelocytic leukemia cells. Alsayed, Y., Modi, S., Uddin, S., Mahmud, N., Druker, B.J., Fish, E.N., Hoffman, R., Platanias, L.C. Exp. Hematol. (2000) [Pubmed]
  19. Interleukin 8 (IL-8) inhibits the interleukin 4 (IL-4)-induced but not the spontaneous growth of human B cells via mechanisms that may involve protein kinase C. Kimata, H., Fujimoto, M., Lindley, I., Furusho, K. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  20. CD16-mediated activation of phosphatidylinositol-3 kinase (PI-3K) in human NK cells involves tyrosine phosphorylation of Cbl and its association with Grb2, Shc, pp36 and p85 PI-3K subunit. Cerboni, C., Gismondi, A., Palmieri, G., Piccoli, M., Frati, L., Santoni, A. Eur. J. Immunol. (1998) [Pubmed]
  21. Protein tyrosine phosphatase inhibitors in Fc gamma RI-induced myeloid oxidant signaling. Erdreich-Epstein, A., Liu, M., Liu, Y., Durden, D.L. Exp. Cell Res. (1997) [Pubmed]
  22. Effect of growth hormone and insulin-like growth factor-I on immunoglobulin production by and growth of human B cells. Kimata, H., Yoshida, A. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
  23. A gibberellin-regulated calcineurin B in rice localizes to the tonoplast and is implicated in vacuole function. Hwang, Y.S., Bethke, P.C., Cheong, Y.H., Chang, H.S., Zhu, T., Jones, R.L. Plant Physiol. (2005) [Pubmed]
  24. The alloantigen-specific immunosuppressive activity of estradiol-chlorambucil conjugate (KM2210) and its beneficial effect on allogeneic bone marrow transplantation in mice. Matsudaira, T., Kodo, H., Okamoto, S., Tani, K., Tojo, A., Ozawa, K., Asano, K., Asano, S. Transplantation (1992) [Pubmed]
  25. CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Reindl, C., Quentmeier, H., Petropoulos, K., Greif, P.A., Benthaus, T., Argiropoulos, B., Mellert, G., Vempati, S., Duyster, J., Buske, C., Bohlander, S.K., Humphries, K.R., Hiddemann, W., Spiekermann, K. Clin. Cancer Res. (2009) [Pubmed]
  26. CSF-1 stimulation induces the formation of a multiprotein complex including CSF-1 receptor, c-Cbl, PI 3-kinase, Crk-II and Grb2. Husson, H., Mograbi, B., Schmid-Antomarchi, H., Fischer, S., Rossi, B. Oncogene (1997) [Pubmed]
  27. Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL). Sattler, M., Salgia, R., Shrikhande, G., Verma, S., Pisick, E., Prasad, K.V., Griffin, J.D. J. Biol. Chem. (1997) [Pubmed]
  28. Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH. Courbard, J.R., Fiore, F., Adélaïde, J., Borg, J.P., Birnbaum, D., Ollendorff, V. J. Biol. Chem. (2002) [Pubmed]
  29. The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells. Lavagna-Sévenier, C., Marchetto, S., Birnbaum, D., Rosnet, O. J. Biol. Chem. (1998) [Pubmed]
  30. CD38-mediated signaling events in murine pro-B cells expressing human CD38 with or without its cytoplasmic domain. Kitanaka, A., Suzuki, T., Ito, C., Nishigaki, H., Coustan-Smith, E., Tanaka, T., Kubota, Y., Campana, D. J. Immunol. (1999) [Pubmed]
  31. Activation-dependent expression of the blood group-related lewis Y antigen on peripheral blood granulocytes. Dettke, M., Pálfi, G., Loibner, H. J. Leukoc. Biol. (2000) [Pubmed]
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