proto oncogene proteins c cbl


Summary: Proto-oncogene proteins that negatively regulate RECEPTOR PROTEIN-TYROSINE KINASE signaling. It is a UBIQUITIN-PROTEIN LIGASE and the cellular homologue of ONCOGENE PROTEIN V-CBL.

Top Publications

  1. Makishima H, Cazzolli H, Szpurka H, Dunbar A, Tiu R, Huh J, et al. Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. J Clin Oncol. 2009;27:6109-16 pubmed publisher
  2. Loh M, Sakai D, Flotho C, Kang M, Fliegauf M, Archambeault S, et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood. 2009;114:1859-63 pubmed publisher
    ..Moreover, the exclusivity of CBL mutations with respect to other Ras pathway-associated mutations indicates that CBL may have a role in deregulating this key pathway in JMML. ..
  3. 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
    ..Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets...
  4. Bandi S, Brandts C, Rensinghoff M, Grundler R, Tickenbrock L, Kohler G, et al. E3 ligase-defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease. Blood. 2009;114:4197-208 pubmed publisher
    ..These findings may explain primary resistance to tyrosine kinase inhibitors targeted at receptor tyrosine kinases...
  5. 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
    ..The study identifies an important signaling pathway linking Cbl-b-induced monoubiquitination to NFkappaB activation in NKT cell anergy induction, which may help design approaches for human cancer therapy. ..
  6. Saur S, Sangkhae V, Geddis A, Kaushansky K, Hitchcock I. Ubiquitination and degradation of the thrombopoietin receptor c-Mpl. Blood. 2010;115:1254-63 pubmed publisher
  7. Grand F, Hidalgo Curtis C, Ernst T, Zoi K, Zoi C, McGuire C, et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood. 2009;113:6182-92 pubmed publisher
    ..We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs. ..
  8. Muramatsu H, Makishima H, Jankowska A, Cazzolli H, O Keefe C, Yoshida N, et al. Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia. Blood. 2010;115:1969-75 pubmed publisher
    ..Our results indicate that mutations in c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting analogous pathogenesis to those observed in chronic myelomonocytic leukemia (CMML) patients. ..
  9. Reindl C, Quentmeier H, Petropoulos K, Greif P, Benthaus T, Argiropoulos B, et al. CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Clin Cancer Res. 2009;15:2238-47 pubmed publisher
    ..This phenotype resembles the one of mutated RTKs and suggests that CBL mutant AML patients might benefit from treatment with FLT3 PTK inhibitors. ..

More Information


  1. 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
  2. Rahimi N. A role for protein ubiquitination in VEGFR-2 signalling and angiogenesis. Biochem Soc Trans. 2009;37:1189-92 pubmed publisher
    ..The present article highlights the recent findings demonstrating a novel role for protein ubiquitination in angiogenesis and its potential in angiogenesis-based therapy. ..
  3. Checquolo S, Palermo R, Cialfi S, Ferrara G, Oliviero C, Talora C, et al. Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia. Oncogene. 2010;29:1463-74 pubmed publisher
    ..Our data indicate that pTalpha/pre-T-cell receptor is able to regulate the different subcellular localization of c-Cbl and, by regulating PKCtheta activity, is also able to influence its ubiquitin ligase activity upon Notch3 protein. ..
  4. Epstein A, Bauer C, Ho A, Bosco G, Zarnescu D. Drosophila Fragile X protein controls cellular proliferation by regulating cbl levels in the ovary. Dev Biol. 2009;330:83-92 pubmed publisher
    ..These data support a model whereby FMRP controls germline proliferation by regulating the expression of cbl in the developing ovary. ..
  5. Patwardhan P, Resh M. Myristoylation and membrane binding regulate c-Src stability and kinase activity. Mol Cell Biol. 2010;30:4094-107 pubmed publisher
    ..All of the pocket mutants exhibited decreased kinase activity. We concluded that myristoylation and the pocket residues regulate c-Src, but in a manner very different from that for c-Abl. ..
  6. Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. Int J Hematol. 2010;91:165-73 pubmed publisher
    ..Moreover, polymorphisms in the JAK2 gene have been recently described as associated with MPN. Additional studies of large cohorts are required to dissect the genetic events in MPNs and the mechanisms of these oncogenic cooperations. ..
  7. Harada Y, Harada Y, Elly C, Ying G, Paik J, Depinho R, et al. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med. 2010;207:1381-91 pubmed publisher
    ..This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation. ..
  8. Shen M, Yen A. c-Cbl tyrosine kinase-binding domain mutant G306E abolishes the interaction of c-Cbl with CD38 and fails to promote retinoic acid-induced cell differentiation and G0 arrest. J Biol Chem. 2009;284:25664-77 pubmed publisher
    ..The results demonstrate the importance of the Gly306 residue in the ability of c-Cbl to propel RA-induced differentiation. ..
  9. Schmitz M. Activation of T cells: releasing the brakes by proteolytic elimination of Cbl-b. Sci Signal. 2009;2:pe38 pubmed publisher
  10. Barresi V, Palumbo G, Musso N, Consoli C, Capizzi C, Meli C, et al. Clonal selection of 11q CN-LOH and CBL gene mutation in a serially studied patient during MDS progression to AML. Leuk Res. 2010;34:1539-42 pubmed publisher
  11. Feldman R, Martinez J. Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR. Biochim Biophys Acta. 2009;1793:1387-94 pubmed publisher
    ..Taken together these results suggest that UDCA may act to suppress cell growth by inhibiting the mitogenic activity of receptor tyrosine kinases such as EGFR through increased receptor degradation. ..
  12. Sproul A, Xu Z, Wilhelm M, Gire S, Greene L. Cbl negatively regulates JNK activation and cell death. Cell Res. 2009;19:950-61 pubmed publisher
    ..Apoptotic stimuli lead to loss of Cbl protein/activity, thereby removing a critical brake on JNK activation and on cell death. ..
  13. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24:1128-38 pubmed publisher
    ..However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation...
  14. Niemeyer C, Kang M, Shin D, Furlan I, Erlacher M, Bunin N, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42:794-800 pubmed publisher
  15. Fiore F, Estebe B, Gibier P, Orsoni J, Courbard J, Chodosh L, et al. Abnormal mammary gland development in MMTV-CBLC transgenic mouse. In Vivo. 2009;23:225-8 pubmed
    ..Alternatively, the phenotype may be due to increased apoptosis. This mouse model may be used to further study regulatory components of the CBL pathway and may be crossed with mice susceptible to develop mammary tumors. ..
  16. Guo X, Nie L, Esmailzadeh L, Zhang J, Bender J, Sadeghi M. Endothelial and smooth muscle-derived neuropilin-like protein regulates platelet-derived growth factor signaling in human vascular smooth muscle cells by modulating receptor ubiquitination. J Biol Chem. 2009;284:29376-82 pubmed publisher
    ..The ESDN effect is mediated, at least in part, through effects on PDGFRbeta ubiquitination. ESDN may serve as a target for regulating PDGFRbeta signaling in VSMCs. ..
  17. Qu X, Zhang Y, Li Y, Hu X, Xu Y, Xu L, et al. Ubiquitin ligase Cbl-b sensitizes leukemia and gastric cancer cells to anthracyclines by activating the mitochondrial pathway and modulating Akt and ERK survival signals. FEBS Lett. 2009;583:2255-62 pubmed publisher
    ..Altogether, these results indicate that Cbl-b sensitized both leukemia and gastric cancer cells to anthracyclines by activating the mitochondrial apoptotic pathway and modulating the ERK and Akt survival pathways. ..
  18. Li Y, Qu X, Qu J, Zhang Y, Liu J, Teng Y, et al. Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation. Cancer Lett. 2009;284:208-15 pubmed publisher
    ..Cbl achieved these effects probably via its regulating PI3K/Akt pathway, and thereby modulated p53 activation. ..
  19. Toffalini F, Kallin A, Vandenberghe P, Pierre P, Michaux L, Cools J, et al. The fusion proteins TEL-PDGFRbeta and FIP1L1-PDGFRalpha escape ubiquitination and degradation. Haematologica. 2009;94:1085-93 pubmed publisher
    ..We have shown that chimeric receptor tyrosine kinases escape ubiquitination and down-regulation and that their stabilization is critical to efficient stimulation of cell proliferation. ..
  20. 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
    ..Combined, these data indicate that Fyn was not required for the induction of central tolerance by negative selection, the adaptor protein role of c-Cbl, or the normal development and function of Treg. ..
  21. Erdreich Epstein A, Liu M, Kant A, Izadi K, Nolta J, Durden D. Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages. J Leukoc Biol. 1999;65:523-34 pubmed
  22. Bacher U, Haferlach C, Schnittger S, Kohlmann A, Kern W, Haferlach T. Mutations of the TET2 and CBL genes: novel molecular markers in myeloid malignancies. Ann Hematol. 2010;89:643-52 pubmed publisher
    ..These novel mutations deepened insights in the mechanisms of leukemogenesis, might contribute to the identification of new therapeutic targets, and improve diagnostics in the myeloid malignancies. ..
  23. Teh C, Daley S, Enders A, Goodnow C. T-cell regulation by casitas B-lineage lymphoma (Cblb) is a critical failsafe against autoimmune disease due to autoimmune regulator (Aire) deficiency. Proc Natl Acad Sci U S A. 2010;107:14709-14 pubmed publisher
  24. Li D, Qu X, Hou K, Zhang Y, Dong Q, Teng Y, et al. PI3K/Akt is involved in bufalin-induced apoptosis in gastric cancer cells. Anticancer Drugs. 2009;20:59-64 pubmed publisher
    ..These results suggested that the PI3K/Akt pathway might play a key role in bufalin-induced apoptosis in gastric cancer MGC803 cells. ..
  25. Azakir B, Angers A. Reciprocal regulation of the ubiquitin ligase Itch and the epidermal growth factor receptor signaling. Cell Signal. 2009;21:1326-36 pubmed publisher
    ..Thus, Itch is a key regulatory locus for EGF receptor degradation. ..
  26. Cai J, Crotty T, Reichert E, Carraway K, Stafforini D, Topham M. Diacylglycerol kinase delta and protein kinase C(alpha) modulate epidermal growth factor receptor abundance and degradation through ubiquitin-specific protease 8. J Biol Chem. 2010;285:6952-9 pubmed publisher
    ..Moreover, the effects of PKCalpha were caused by its inhibition of Akt, which stabilizes USP8. Our data indicate a novel mechanism where DGKdelta and PKCalpha modulate the levels of ubiquitinated EGFR through Akt and USP8. ..
  27. Jung J, Lee J, Kim J, Lee S, You G, Park S, et al. Quercetin suppresses HeLa cell viability via AMPK-induced HSP70 and EGFR down-regulation. J Cell Physiol. 2010;223:408-14 pubmed publisher
    ..Together, these results suggest that quercetin may have anti-tumor effects on HeLa cells via AMPK-induced HSP70 and down-regulation of EGFR. ..
  28. Huang H, Jeon M, Liao L, Yang C, Elly C, Yates J, et al. K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling. Immunity. 2010;33:60-70 pubmed publisher
    ..Thus, the present study reveals unconventional K33-linked polyubiquitination in nonproteolytic regulation of cell-surface-receptor-mediated signal transduction. ..
  29. Orinska Z, Föger N, Huber M, Marschall J, Mirghomizadeh F, Du X, et al. I787 provides signals for c-Kit receptor internalization and functionality that control mast cell survival and development. Blood. 2010;116:2665-75 pubmed publisher
    ..Thus, I787 provides nonredundant signals for c-Kit internalization and functionality. ..
  30. Salingcarnboriboon R, Pavasant P, Noda M. Cbl-b enhances Runx2 protein stability and augments osteocalcin promoter activity in osteoblastic cell lines. J Cell Physiol. 2010;224:743-7 pubmed publisher
    ..Moreover, the upregulation of downstream genes of Runx2 such as osteocalcin and alkaline phosphatase mRNA was also observed. These data propose the involvement of Cbl-b in the regulation of osteoblast-related genes expression. ..
  31. Naramura M, Nandwani N, Gu H, Band V, Band H. Rapidly fatal myeloproliferative disorders in mice with deletion of Casitas B-cell lymphoma (Cbl) and Cbl-b in hematopoietic stem cells. Proc Natl Acad Sci U S A. 2010;107:16274-9 pubmed publisher
    ..Thus, Cbl and Cbl-b play redundant but essential roles in HSC regulation, whose breakdown leads to hematological abnormalities that phenocopy crucial aspects of mutant Cbl-driven human myeloid malignancies...
  32. Jacob M, Todd L, Majumdar R, Li Y, Yamamoto K, Pure E. Endogenous cAbl regulates receptor endocytosis. Cell Signal. 2009;21:1308-16 pubmed publisher
    ..Our results thus indicate that CrkII links receptor engagement to cytoskeletal remodeling by coupling cCbl- and cAbl-mediated signaling pathways that cooperatively regulate ligand-induced receptor endocytosis. ..
  33. 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
    ..Thus, both c-Cbl and Cbl-b promote bone resorption via the stabilization of microtubules, allowing the formation of the podosome belt in osteoclasts, and by promoting osteoclast survival. ..
  34. Song J, Szczepanski M, Kim S, Kim J, An J, Kwon Y, et al. c-Cbl-mediated degradation of TRAIL receptors is responsible for the development of the early phase of TRAIL resistance. Cell Signal. 2010;22:553-63 pubmed publisher
  35. Qu X, Li Y, Liu J, Xu L, Zhang Y, Hu X, et al. Cbl-b promotes chemotherapy-induced apoptosis in rat basophilic leukemia cells by suppressing PI3K/Akt activation and enhancing MEK/ERK activation. Mol Cell Biochem. 2010;340:107-14 pubmed publisher
    ..The consistent results were also showed in the process of Ara-c treatment. These observations indicate that Cbl-b promotes RBL-2H3 apoptosis induced by VP-16 or Ara-c, probably through inhibition of Akt and activation of ERK. ..
  36. Aguado R, Martin Blanco N, Caraballo M, Canelles M. The endocytic adaptor Numb regulates thymus size by modulating pre-TCR signaling during asymmetric division. Blood. 2010;116:1705-14 pubmed publisher
    ..The conclusion is that Numb determines the levels of pre-TCR signaling in dividing thymocytes and, ultimately, the size of the pool from which mature T lymphocytes are selected. ..
  37. Cone R, Chattopadhyay S, Sharafieh R, Lemire Y, O Rourke J, Flavell R, et al. T cell sensitivity to TGF-beta is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber. Int Immunol. 2009;21:567-74 pubmed publisher
  38. Roepstorff K, Grandal M, Henriksen L, Knudsen S, Lerdrup M, Grøvdal L, et al. Differential effects of EGFR ligands on endocytic sorting of the receptor. Traffic. 2009;10:1115-27 pubmed publisher
    ..The Cbl ubiquitin ligases, especially c-Cbl, are responsible for EGFR ubiquitination after stimulation with all ligands, and persistent EGFR phosphorylation and ubiquitination largely correlate with receptor degradation. ..
  39. Kales S, Ryan P, Nau M, Lipkowitz S. Cbl and human myeloid neoplasms: the Cbl oncogene comes of age. Cancer Res. 2010;70:4789-94 pubmed publisher
    ..These data also provide insight into potential therapeutic approaches to myeloid disorders harboring Cbl mutations. ..
  40. Truitt L, Freywald T, Decoteau J, Sharfe N, Freywald A. The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells. Cancer Res. 2010;70:1141-53 pubmed publisher
  41. Kim H, Das A, Gross C, Bryceson Y, Long E. Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase. Immunity. 2010;32:175-86 pubmed publisher
    ..Therefore, NK cell activation by synergizing receptors is regulated at the level of Vav1 by a hierarchy of inhibitory mechanisms. ..
  42. Ryan P, Sivadasan Nair N, Nau M, Nicholas S, Lipkowitz S. The N terminus of Cbl-c regulates ubiquitin ligase activity by modulating affinity for the ubiquitin-conjugating enzyme. J Biol Chem. 2010;285:23687-98 pubmed publisher
    ..These data suggest that the N terminus of Cbl-c contributes to the binding to the E2 and that phosphorylation of Tyr-341 leads to a decrease in affinity and an increase in the E3 activity of Cbl-c. ..
  43. Rumi E, Elena C, Passamonti F. Mutational status of myeloproliferative neoplasms. Crit Rev Eukaryot Gene Expr. 2010;20:61-76 pubmed
    ..Implications of these mutations in the understanding of the pathogenesis of myeloproliferative neoplasms and in the clinical phenotype are discussed in this review. ..
  44. Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010;87:250-7 pubmed publisher
    ..These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies...
  45. Adams C, Housley W, Bhowmick S, Cone R, Rajan T, Forouhar F, et al. Cbl-b(-/-) T cells demonstrate in vivo resistance to regulatory T cells but a context-dependent resistance to TGF-beta. J Immunol. 2010;185:2051-8 pubmed publisher
  46. Thien C, Dagger S, Steer J, Koentgen F, Jansen E, Scott C, et al. c-Cbl promotes T cell receptor-induced thymocyte apoptosis by activating the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem. 2010;285:10969-81 pubmed publisher
    ..These findings identify tyrosine-phosphorylated c-Cbl as a critical sensor of TCR signal strength that regulates the engagement of death-promoting signals. ..
  47. Beer P, Delhommeau F, LeCouedic J, Dawson M, Chen E, Bareford D, et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 2010;115:2891-900 pubmed publisher
  48. Daniel J, Dangelmaier C, Mada S, Buitrago L, Jin J, Langdon W, et al. Cbl-b is a novel physiologic regulator of glycoprotein VI-dependent platelet activation. J Biol Chem. 2010;285:17282-91 pubmed publisher
    ..These data indicate that Cbl-b plays a positive modulatory role in GPVI-dependent platelet signaling, which translates to an important regulatory role in hemostasis and thrombosis in vivo. ..
  49. Covani U, Marconcini S, Derchi G, Barone A, Giacomelli L. Relationship between human periodontitis and type 2 diabetes at a genomic level: a data-mining study. J Periodontol. 2009;80:1265-73 pubmed publisher
    ..In particular, the shared leader genes could have an important role in this relationship, which may be investigated further with targeted experimentation. ..
  50. Wang Y, Chen Z, Bergmann A. Regulation of EGFR and Notch signaling by distinct isoforms of D-cbl during Drosophila development. Dev Biol. 2010;342:1-10 pubmed publisher
    ..Taken together, these data suggest that D-Cbl controls the EGFR and Notch/Delta signaling pathways through production of two alternatively spliced isoforms during development in Drosophila. ..
  51. Guy G, Jackson R, Yusoff P, Chow S. Sprouty proteins: modified modulators, matchmakers or missing links?. J Endocrinol. 2009;203:191-202 pubmed publisher
    ..With such stringent control of the Sproutys, the main question is what key proteins does this facilitator bring together? ..
  52. Yang T, Martin M, Nielsen J, Milne K, Wall E, Lin W, et al. Mammary tumors with diverse immunological phenotypes show differing sensitivity to adoptively transferred CD8+ T cells lacking the Cbl-b gene. Cancer Immunol Immunother. 2009;58:1865-75 pubmed publisher
    ..Thus, Cbl-b-null CD8+ T cells are generally more efficacious but are nonetheless unable to mediate curative responses against all tumor phenotypes. ..
  53. Wang H, Holst J, Woo S, Guy C, Bettini M, Wang Y, et al. Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development. EMBO J. 2010;29:1285-98 pubmed publisher
    ..Thus, tonic TCR:CD3 ubiquitylation results in precise regulation of TCR expression on immature T cells, which is required to maintain the fidelity of T-cell development. ..