CBL

Summary

Gene Symbol: CBL
Description: Cbl proto-oncogene
Alias: C-CBL, CBL2, FRA11B, NSLL, RNF55, E3 ubiquitin-protein ligase CBL, Cas-Br-M (murine) ecotropic retroviral transforming sequence, Cbl proto-oncogene, E3 ubiquitin protein ligase, RING finger protein 55, RING-type E3 ubiquitin transferase CBL, casitas B-lineage lymphoma proto-oncogene, fragile site, folic acid type, rare, fra(11)(q23.3), oncogene CBL2, proto-oncogene c-Cbl, signal transduction protein CBL
Species: human
Products:     CBL

Top Publications

  1. Joazeiro C, Wing S, Huang H, Leverson J, Hunter T, Liu Y. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science. 1999;286:309-12 pubmed
    ..c-Cbl, an adapter protein for RPTKs, positively regulates RPTK ubiquitination in a manner dependent on its variant SRC ..
  2. Levkowitz G, Waterman H, Ettenberg S, Katz M, Tsygankov A, Alroy I, et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell. 1999;4:1029-40 pubmed
    ..An in vitro reconstituted system indicates that Cbl adaptor proteins directly control downregulation of the receptor for the epidermal growth factor (EGFR) by ..
  3. Wu W, Tu S, Cerione R. Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation. Cell. 2003;114:715-25 pubmed
    ..Here, we show that activation of Cdc42 protects the EGF receptor from the negative regulatory activity of the c-Cbl ubiquitin ligase...
  4. 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...
  5. Kim M, Tezuka T, Tanaka K, Yamamoto T. Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Oncogene. 2004;23:1645-55 pubmed
    The Cbl family proteins Cbl, Cbl-b, and Cbl-c/Cbl-3 are thought to regulate signaling through protein-tyrosine kinases, positively as scaffold proteins and negatively as ubiquitin ligases...
  6. Gelsi Boyer V, Trouplin V, Roquain J, Adélaïde J, Carbuccia N, Esterni B, et al. ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. Br J Haematol. 2010;151:365-75 pubmed publisher
    ..using array-comparative genomic hybridisation (aCGH) and sequencing of 13 candidate genes including ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, PTPN11, RUNX1, TET2 and WT1...
  7. Kirsch K, Georgescu M, Shishido T, Langdon W, Birge R, Hanafusa H. The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction. J Biol Chem. 2001;276:4957-63 pubmed
    ..bound specifically to a tyrosine-phosphorylated protein of 120 kDa, which we identified as the proto-oncoprotein c-Cbl. The c-Cbl-binding site for CMS mapped to the carboxyl terminus of c-Cbl and is different from the proline-rich ..
  8. Bao J, Gur G, Yarden Y. Src promotes destruction of c-Cbl: implications for oncogenic synergy between Src and growth factor receptors. Proc Natl Acad Sci U S A. 2003;100:2438-43 pubmed
    ..The underlying mechanism involves inhibition of the normal, c-Cbl-regulated process of ligand-induced receptor down-regulation...
  9. Feng L, Wang J, Jin H, Qian K, Geng J. SH3KBP1-binding protein 1 prevents epidermal growth factor receptor degradation by the interruption of c-Cbl-CIN85 complex. Cell Biochem Funct. 2011;29:589-96 pubmed publisher
    The binding of Cbl-interacting protein of 85?kDa (CIN85) to c-Cbl is important to endocytosis and degradation of epidermal growth factor receptor (EGFR)...

More Information

Publications103 found, 100 shown here

  1. Teckchandani A, Feshchenko E, Tsygankov A. c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases. Oncogene. 2001;20:1739-55 pubmed
    The protooncogenic protein c-Cbl has been shown to act as a multivalent adaptor and a negative regulator of protein tyrosine kinase-mediated signaling. Recent studies have implicated it in the regulation of cell adhesion-related events...
  2. Waterman H, Levkowitz G, Alroy I, Yarden Y. The RING finger of c-Cbl mediates desensitization of the epidermal growth factor receptor. J Biol Chem. 1999;274:22151-4 pubmed
    ..c-Cbl, a tyrosine phosphorylation substrate shared by several signaling pathways, accelerates desensitization by ..
  3. Zuo W, Huang F, Chiang Y, Li M, Du J, Ding Y, et al. c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-? type II receptor. Mol Cell. 2013;49:499-510 pubmed publisher
    ..Here, we show that Casitas B-lineage lymphoma (c-Cbl), a known proto-oncogene encoding an ubiquitin E3 ligase, promotes TGF-? signaling by neddylating and stabilizing ..
  4. Sargin B, Choudhary C, Crosetto N, Schmidt M, Grundler R, Rensinghoff M, et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood. 2007;110:1004-12 pubmed
    ..However, little is known about a possible role of highly expressed wild-type Flt3 in AML. The proto-oncogene c-Cbl is an important regulator of RTK signaling, acting through its ubiquitin ligase activity and as a platform for ..
  5. Fernandes M, Reddy M, Croteau N, Walz C, Weisbach H, Podar K, et al. Novel oncogenic mutations of CBL in human acute myeloid leukemia that activate growth and survival pathways depend on increased metabolism. J Biol Chem. 2010;285:32596-605 pubmed publisher
    ..gain-of-function mutations in the ? helical structure within the linker sequence of the E3 ubiquitin ligase CBL have been associated with AML...
  6. Ng C, Jackson R, Buschdorf J, Sun Q, Guy G, Sivaraman J. Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates. EMBO J. 2008;27:804-16 pubmed publisher
    The c-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination...
  7. Knight J, Shepherd C, Rizzo S, Brewer D, Jhavar S, Dodson A, et al. TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer. Br J Cancer. 2008;99:1849-58 pubmed publisher
    ..The transcription factor TEAD1 and the ubiquitin ligase c-Cbl were identified as novel basal cell markers...
  8. Chandra V, Kalia M, Hajela K, Jameel S. The ORF3 protein of hepatitis E virus delays degradation of activated growth factor receptors by interacting with CIN85 and blocking formation of the Cbl-CIN85 complex. J Virol. 2010;84:3857-67 pubmed publisher
    ..The ORF3 protein was found to interact with CIN85, a multidomain adaptor protein implicated in the Cbl-mediated downregulation of receptor tyrosine kinases...
  9. Ota S, Hazeki K, Rao N, Lupher M, Andoniou C, Druker B, et al. The RING finger domain of Cbl is essential for negative regulation of the Syk tyrosine kinase. J Biol Chem. 2000;275:414-22 pubmed
    The proto-oncogene product Cbl has emerged as a negative regulator of a number of protein-tyrosine kinases, including the ZAP-70/Syk tyrosine kinases that are critical for signaling in hematopoietic cells...
  10. 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) ..
  11. Rao N, Lupher M, Ota S, Reedquist K, Druker B, Band H. The linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells. J Immunol. 2000;164:4616-26 pubmed
    The protooncogene product Cbl has emerged as a negative regulator of tyrosine kinases. We have shown previously that Cbl binds to ZAP-70 through its N-terminal tyrosine kinase binding (TKB) domain...
  12. Kassenbrock C, Anderson S. Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations. J Biol Chem. 2004;279:28017-27 pubmed
    c-Cbl down-regulates receptor tyrosine kinases by conjugating ubiquitin to them, leading to receptor internalization and degradation...
  13. Yang P, Henderson A. Nef enhances c-Cbl phosphorylation in HIV-infected CD4+ T lymphocytes. Virology. 2005;336:219-28 pubmed
    ..This Nef-induced phosphorylation was observed in unstimulated cells, and c-Cbl was identified as one of the proteins whose phosphorylation was upregulated by Nef...
  14. Haglund K, Schmidt M, Wong E, Guy G, Dikic I. Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation. EMBO Rep. 2005;6:635-41 pubmed
    The ubiquitin ligase Cbl mediates ubiquitination of activated receptor tyrosine kinases (RTKs) and interacts with endocytic scaffold complexes, including CIN85/endophilins, to facilitate RTK endocytosis and degradation...
  15. Dunbar A, Gondek L, O Keefe C, Makishima H, Rataul M, Szpurka H, et al. 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res. 2008;68:10349-57 pubmed publisher
    ..both known and unknown pathogenic mutations, including newly identified missense mutations in the proto-oncogene c-Cbl in 7 of 12 patients with UPD11q...
  16. Valiya Veettil M, Sadagopan S, Kerur N, Chakraborty S, Chandran B. Interaction of c-Cbl with myosin IIA regulates Bleb associated macropinocytosis of Kaposi's sarcoma-associated herpesvirus. PLoS Pathog. 2010;6:e1001238 pubmed publisher
    ..Here we demonstrate that tyrosine phosphorylation of the adaptor protein c-Cbl is required for KSHV induced membrane blebbing and macropinocytosis...
  17. Ettenberg S, Keane M, Nau M, Frankel M, Wang L, Pierce J, et al. cbl-b inhibits epidermal growth factor receptor signaling. Oncogene. 1999;18:1855-66 pubmed
    The role of cbl-b in signaling by the epidermal growth factor receptor (EGFR) was studied and compared with c-cbl...
  18. Kowanetz K, Husnjak K, Höller D, Kowanetz M, Soubeyran P, Hirsch D, et al. CIN85 associates with multiple effectors controlling intracellular trafficking of epidermal growth factor receptors. Mol Biol Cell. 2004;15:3155-66 pubmed
    CIN85 is a multidomain adaptor protein involved in Cbl-mediated down-regulation of epidermal growth factor (EGF) receptors...
  19. Hu J, Hubbard S. Structural characterization of a novel Cbl phosphotyrosine recognition motif in the APS family of adapter proteins. J Biol Chem. 2005;280:18943-9 pubmed
    The Cbl adapter proteins typically function to down-regulate activated protein tyrosine kinases and other signaling proteins by coupling them to the ubiquitination machinery for degradation by the proteasome...
  20. Schulze W, Deng L, Mann M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol Syst Biol. 2005;1:2005.0008 pubmed
    ..Our results demonstrate that system-wide mapping of peptide-protein interactions sites is possible, and suggest shared and unique roles of ErbB-receptor family members in downstream signaling. ..
  21. Andoniou C, Lill N, Thien C, Lupher M, Ota S, Bowtell D, et al. The Cbl proto-oncogene product negatively regulates the Src-family tyrosine kinase Fyn by enhancing its degradation. Mol Cell Biol. 2000;20:851-67 pubmed
    ..We have investigated the possibility that the tyrosine kinase regulatory protein Cbl provides a complementary mechanism of Fyn regulation...
  22. Burke P, Schooler K, Wiley H. Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking. Mol Biol Cell. 2001;12:1897-910 pubmed
    ..During the inactivation phase, c-Cbl became EGFR associated, consistent with its postulated role in receptor attenuation...
  23. Kant A, De P, Peng X, Yi T, Rawlings D, Kim J, et al. SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC. Blood. 2002;100:1852-9 pubmed
    ..Stimulation with sensitized sheep red blood cells (sRBCs) induced tyrosine phosphorylation of CBL and association of CBL with CRKL...
  24. Schmidt M, Husnjak K, Szymkiewicz I, Haglund K, Dikic I. Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule betaPix. Oncogene. 2006;25:3071-8 pubmed
    ..Recently, it has been shown that betaPix/Cool-1 associates with the ubiquitin ligase Cbl, which appears to be a critical step in Cdc42-mediated inhibition of epidermal-growth-factor-receptor (EGFR) ..
  25. Waterman H, Katz M, Rubin C, Shtiegman K, Lavi S, Elson A, et al. A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling. EMBO J. 2002;21:303-13 pubmed
    Ligand-induced desensitization of the epidermal growth factor receptor (EGFR) is controlled by c-Cbl, a ubiquitin ligase that binds multiple signaling proteins, including the Grb2 adaptor...
  26. Rubin C, Litvak V, Medvedovsky H, Zwang Y, Lev S, Yarden Y. Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops. Curr Biol. 2003;13:297-307 pubmed
    ..c-Cbl is an adaptor that modulates this process by recruiting binding partners, such as ubiquitin-conjugating enzymes...
  27. Tibaldi E, Reinherz E. CD2BP3, CIN85 and the structurally related adaptor protein CMS bind to the same CD2 cytoplasmic segment, but elicit divergent functional activities. Int Immunol. 2003;15:313-29 pubmed
    ..CIN85/CD2BP3 themselves as evidenced by mAb accessibility analysis and protein interaction studies including c-Cbl binding. This form of intramolecular regulation is not manifest by CMS...
  28. Adachi S, Shimizu M, Shirakami Y, Yamauchi J, Natsume H, Matsushima Nishiwaki R, et al. (-)-Epigallocatechin gallate downregulates EGF receptor via phosphorylation at Ser1046/1047 by p38 MAPK in colon cancer cells. Carcinogenesis. 2009;30:1544-52 pubmed publisher
    ..Prolonged exposure to EGCG caused EGFR degradation. However, EGCG required neither an ubiquitin ligase (c-Cbl) binding to EGFR nor a phosphorylation of EGFR at tyrosine residues, both of which are reportedly necessary for ..
  29. Visser Smit G, Place T, Cole S, Clausen K, Vemuganti S, Zhang G, et al. Cbl controls EGFR fate by regulating early endosome fusion. Sci Signal. 2009;2:ra86 pubmed publisher
    Amino acid residues 1 to 434 of the E3 ubiquitin ligase Cbl control signaling of the epidermal growth factor receptor (EGFR) by enhancing its ubiquitination, down-regulation, and lysosomal degradation...
  30. 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
    b>Cbl is a cytosolic protein that is rapidly tyrosine phosphorylated in response to Fc receptor activation and binds to the adaptor proteins Grb2, CrkL, and Nck. A few reports describe Cbl interactions in primary human hematopoietic cells...
  31. Jozic D, Cárdenes N, Deribe Y, Moncalian G, Hoeller D, Groemping Y, et al. Cbl promotes clustering of endocytic adaptor proteins. Nat Struct Mol Biol. 2005;12:972-9 pubmed
    The ubiquitin ligases c-Cbl and Cbl-b play a crucial role in receptor downregulation by mediating multiple monoubiquitination of receptors and promoting their sorting for lysosomal degradation...
  32. Peschard P, Kozlov G, Lin T, Mirza I, Berghuis A, Lipkowitz S, et al. Structural basis for ubiquitin-mediated dimerization and activation of the ubiquitin protein ligase Cbl-b. Mol Cell. 2007;27:474-85 pubmed
    b>Cbl proteins are E3 ubiquitin ligases that are negative regulators of many receptor tyrosine kinases...
  33. Umebayashi K, Stenmark H, Yoshimori T. Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation. Mol Biol Cell. 2008;19:3454-62 pubmed publisher
    c-Cbl is the E3 ubiquitin ligase that ubiquitinates the epidermal growth factor (EGF) receptor (EGFR)...
  34. 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
    ..Recurrent UPD11q led to identification of homozygous mutations in c-Cbl, an E3 ubiquitin ligase involved in attenuation of proliferative signals transduced by activated receptor tyrosine ..
  35. Khan E, Lanir R, Danielson A, Goldkorn T. Epidermal growth factor receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking. FASEB J. 2008;22:910-7 pubmed
    ..phosphorylation of the epidermal growth factor receptor (EGFR), resulting in the lack of ubiquitination by c-Cbl, and impaired degradation...
  36. Yan S, Liu Y, Zhang L, Qu J, Xu L, Liu J, et al. Ubiquitin ligase c-Cbl is involved in tamoxifen-induced apoptosis of MCF-7 cells by downregulating the survival signals. Acta Oncol. 2011;50:693-9 pubmed publisher
    ..In the present study, we investigated the roles of c-Src, ERK, AKT and c-Cbl ubiquitin ligases during TAM-induced apoptosis of MCF-7 cells...
  37. Tang J, Sawasdikosol S, Chang J, Burakoff S. SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling. Proc Natl Acad Sci U S A. 1999;96:9775-80 pubmed
    ..such as SLP-76, Vav, and LAT, positively regulate TCR-mediated signal transduction, whereas others, such as Cbl, play an inhibitory role...
  38. Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon W, Dikic I. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature. 2002;416:183-7 pubmed
    b>Cbl is a multi-adaptor protein involved in ligand-induced downregulation of receptor tyrosine kinases...
  39. Kozlov G, Peschard P, Zimmerman B, Lin T, Moldoveanu T, Mansur Azzam N, et al. Structural basis for UBA-mediated dimerization of c-Cbl ubiquitin ligase. J Biol Chem. 2007;282:27547-55 pubmed
    Ligand-induced down-regulation by the ubiquitin-protein ligases, c-Cbl and Cbl-b, controls signaling downstream from many receptor-tyrosine kinases (RTK)...
  40. 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
    ..In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 ..
  41. 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
    ..Using single nucleotide polymorphism arrays, we identified a region of 11q isodisomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations in 27 of 159 JMML samples...
  42. Duan L, Raja S, Chen G, Virmani S, Williams S, Clubb R, et al. Negative regulation of EGFR-Vav2 signaling axis by Cbl ubiquitin ligase controls EGF receptor-mediated epithelial cell adherens junction dynamics and cell migration. J Biol Chem. 2011;286:620-33 pubmed publisher
    The E3 ubiquitin ligase Casitas B lymphoma protein (Cbl) controls the ubiquitin-dependent degradation of EGF receptor (EGFR), but its role in regulating downstream signaling elements with which it associates and its impact on biological ..
  43. Dou H, Buetow L, Sibbet G, Cameron K, Huang D. Essentiality of a non-RING element in priming donor ubiquitin for catalysis by a monomeric E3. Nat Struct Mol Biol. 2013;20:982-986 pubmed publisher
    ..Here, we present a crystal structure of a monomeric RING E3, Tyr363-phosphorylated human CBL-B, bound to a stabilized Ub-linked E2, revealing a similar mechanism in activating E2~Ub...
  44. Schmidt M, Hoeller D, Yu J, Furnari F, Cavenee W, Dikic I, et al. Alix/AIP1 antagonizes epidermal growth factor receptor downregulation by the Cbl-SETA/CIN85 complex. Mol Cell Biol. 2004;24:8981-93 pubmed
    The assembly of the Cbl-SETA/CIN85-endophilin complex at the C terminus of the epidermal growth factor receptor (EGFR) following ligand activation mediates its internalization and ubiquitination...
  45. Grøvdal L, Stang E, Sorkin A, Madshus I. Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation. Exp Cell Res. 2004;300:388-95 pubmed
    Mutation of the binding site for Cbl (Tyr1045) in the EGF receptor (EGFR) results in impaired ubiquitination but does not affect EGFR internalization...
  46. Kaabeche K, Guenou H, Bouvard D, Didelot N, Listrat A, Marie P. Cbl-mediated ubiquitination of alpha5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation. J Cell Sci. 2005;118:1223-32 pubmed
    ..Immunoprecipitation analysis showed that alpha5 integrin interacts with both the E3 ubiquitin ligase Cbl and ubiquitin...
  47. Pennock S, Wang Z. A tale of two Cbls: interplay of c-Cbl and Cbl-b in epidermal growth factor receptor downregulation. Mol Cell Biol. 2008;28:3020-37 pubmed publisher
    The precise role of Cbl in epidermal growth factor (EGF) receptor (EGFR) endocytosis and trafficking remains to be fully uncovered...
  48. Schroeder B, Weller S, Chen J, BILLADEAU D, McNiven M. A Dyn2-CIN85 complex mediates degradative traffic of the EGFR by regulation of late endosomal budding. EMBO J. 2010;29:3039-53 pubmed publisher
    ..The adaptor protein CIN85 (cbl-interacting protein of 85 kDa), which has been proposed to indirectly link the EGFR to the endocytic machinery at ..
  49. Dou H, Buetow L, Hock A, Sibbet G, Vousden K, Huang D. Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl. Nat Struct Mol Biol. 2012;19:184-92 pubmed publisher
    Cbls are RING ubiquitin ligases that attenuate receptor tyrosine kinase (RTK) signal transduction. Cbl ubiquitination activity is stimulated by phosphorylation of a linker helix region (LHR) tyrosine residue...
  50. Kang J, Park S, Hong H, Jeong J, Kim H, Kim S. CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-? signaling. Oncogene. 2012;31:5123-31 pubmed publisher
    Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types...
  51. Meng W, Sawasdikosol S, Burakoff S, Eck M. Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature. 1999;398:84-90 pubmed
    b>Cbl is an adaptor protein that functions as a negative regulator of many signalling pathways that start from receptors at the cell surface...
  52. Zheng N, Wang P, Jeffrey P, Pavletich N. Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell. 2000;102:533-9 pubmed
    Ubiquitin-protein ligases (E3s) regulate diverse cellular processes by mediating protein ubiquitination. The c-Cbl proto-oncogene is a RING family E3 that recognizes activated receptor tyrosine kinases, promotes their ubiquitination by a ..
  53. Jiang X, Sorkin A. Epidermal growth factor receptor internalization through clathrin-coated pits requires Cbl RING finger and proline-rich domains but not receptor polyubiquitylation. Traffic. 2003;4:529-43 pubmed
    b>Cbl proteins have been implicated in the regulation of endocytic trafficking of epidermal growth factor receptor. However, the precise role of Cbl in epidermal growth factor receptor endocytosis is not defined...
  54. 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...
  55. Huang F, Sorkin A. Growth factor receptor binding protein 2-mediated recruitment of the RING domain of Cbl to the epidermal growth factor receptor is essential and sufficient to support receptor endocytosis. Mol Biol Cell. 2005;16:1268-81 pubmed
    ..Overexpression of Grb2-binding protein c-Cbl did not restore endocytosis in Grb2-depleted cells...
  56. Scott R, Eketjäll S, Aineskog H, Ibanez C. Distinct turnover of alternatively spliced isoforms of the RET kinase receptor mediated by differential recruitment of the Cbl ubiquitin ligase. J Biol Chem. 2005;280:13442-9 pubmed
    ..Here we demonstrated that activated RET51 associated more strongly with the ubiquitin ligase Cbl than did RET9, leading to increased ubiquitylation and faster turnover of RET51...
  57. Singh A, Meyer R, Navruzbekov G, Shelke R, Duan L, Band H, et al. A critical role for the E3-ligase activity of c-Cbl in VEGFR-2-mediated PLCgamma1 activation and angiogenesis. Proc Natl Acad Sci U S A. 2007;104:5413-8 pubmed
    ..Here by using in vitro and in vivo binding assays, we show that the Casitas B-lineage lymphoma (c-Cbl) E3 ubiquitin ligase constitutively associates with PLCgamma1 via its C-terminal domain and conditionally interacts ..
  58. 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 ..
  59. Okur M, Ooi J, Fong C, Martinez N, Garcia Dominguez C, Rojas J, et al. Intersectin 1 enhances Cbl ubiquitylation of epidermal growth factor receptor through regulation of Sprouty2-Cbl interaction. Mol Cell Biol. 2012;32:817-25 pubmed publisher
    ..stimulates ubiquitylation of the epidermal growth factor receptor (EGFR) through enhancing the activity of the Cbl E3 ubiquitin ligase. However, the precise mechanism through which ITSN1 enhances Cbl activity was unclear...
  60. Wong E, Lim J, Low B, Chen Q, Guy G. Evidence for direct interaction between Sprouty and Cbl. J Biol Chem. 2001;276:5866-75 pubmed
    ..Here, we demonstrate that hSPRY2 associates directly with c-Cbl, a known down-regulator of RTK signaling...
  61. 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
    b>CBL is a negative regulator of activated receptor tyrosine kinases (RTK). In this study, we determined the frequency of CBL mutations in acute leukemias and evaluated the oncogenic potential of mutant CBL...
  62. Tan Y, Krishnaswamy S, Nandi S, Kanteti R, Vora S, Onel K, et al. CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases. PLoS ONE. 2010;5:e8972 pubmed publisher
    ..c-CBL is an E3 ubiquitin ligase and adaptor molecule important in normal homeostasis and cancer...
  63. 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
    ..Recently, mutations of the tet oncogene family member 2 (TET2) and Casitas B-cell lymphoma (CBL) genes became the focus of interest...
  64. van Leeuwen J, Paik P, Samelson L. Activation of nuclear factor of activated T cells-(NFAT) and activating protein 1 (AP-1) by oncogenic 70Z Cbl requires an intact phosphotyrosine binding domain but not Crk(L) or p85 phosphatidylinositol 3-kinase association. J Biol Chem. 1999;274:5153-62 pubmed
    The Cbl proto-oncogene product is a complex adapter protein that functions as a negative regulator of protein tyrosine kinases...
  65. Petrelli A, Gilestro G, Lanzardo S, Comoglio P, Migone N, Giordano S. The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature. 2002;416:187-90 pubmed
    ..Here we demonstrate that a complex involving endophilins, CIN85 and Cbl controls this process. Endophilins are regulatory components of clathrin-coated vesicle formation...
  66. Schmidt M, Chen B, Randazzo L, Bogler O. SETA/CIN85/Ruk and its binding partner AIP1 associate with diverse cytoskeletal elements, including FAKs, and modulate cell adhesion. J Cell Sci. 2003;116:2845-55 pubmed
    ..regulating diverse signal transduction pathways, including the internalization of tyrosine kinase receptors via the Cbl ubiquitin ligases, and attenuating PI3K activity by interaction with its regulatory subunit...
  67. Kowanetz K, Crosetto N, Haglund K, Schmidt M, Heldin C, Dikic I. Suppressors of T-cell receptor signaling Sts-1 and Sts-2 bind to Cbl and inhibit endocytosis of receptor tyrosine kinases. J Biol Chem. 2004;279:32786-95 pubmed
    The ubiquitin (Ub) ligase Cbl plays a critical role in attenuation of receptor tyrosine kinase (RTK) signaling by inducing ubiquitination of RTKs and promoting their sorting for endosomal degradation...
  68. Ravid T, Heidinger J, Gee P, Khan E, Goldkorn T. c-Cbl-mediated ubiquitinylation is required for epidermal growth factor receptor exit from the early endosomes. J Biol Chem. 2004;279:37153-62 pubmed
    ..In the present study we examined the role of the E3 ligase c-Cbl, as a possible link between oxidative stress, EGFR signaling, and tumorigenic responses...
  69. Simmons A, Gangadharan B, Hodges A, Sharrocks K, Prabhakar S, Garcia A, et al. Nef-mediated lipid raft exclusion of UbcH7 inhibits Cbl activity in T cells to positively regulate signaling. Immunity. 2005;23:621-34 pubmed
    ..Here, the E2 ubiquitin-conjugating enzyme UbcH7, which acts in conjunction with c-Cbl, is absent from lipid rafts...
  70. Nam J, Onodera Y, Mazaki Y, Miyoshi H, Hashimoto S, Sabe H. CIN85, a Cbl-interacting protein, is a component of AMAP1-mediated breast cancer invasion machinery. EMBO J. 2007;26:647-56 pubmed
    ..A mouse ortholog of AMAP1, ASAP1, is known to bind to CIN85, a binding partner of an E3 ligase, Cbl. Here, we found that CIN85 colocalizes with AMAP1 at invadopodia, and binding of AMAP1 with CIN85 is important for ..
  71. Zhang J, Zheng X, Yang X, Liao K. CIN85 associates with endosomal membrane and binds phosphatidic acid. Cell Res. 2009;19:733-46 pubmed publisher
    CIN85 (Cbl-interacting protein of 85 kDa) is an important molecule involved in receptor tyrosine kinase endocytosis...
  72. 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
    ..somatic uniparental disomy 11q was detected in 4 of 49 patients; all of these cases harbored RING finger domain c-Cbl mutations. In total, c-Cbl mutations were detected in 5 (10%) of 49 patients...
  73. Chakraborty S, Veettil M, Bottero V, Chandran B. Kaposi's sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection. Proc Natl Acad Sci U S A. 2012;109:E1163-72 pubmed publisher
    ..KSHV infection activated c-Cbl, which induced the selective translocation of KSHV into lipid rafts (LRs) along with the ?3?1, ?V?3, and xCT ..
  74. Hazeki K, Hazeki O, Matsuo T, Seya T, Yamashita T, Nagasawa S, et al. Role of Syk in Fc gamma receptor-coupled tyrosine phosphorylation of Cbl in a manner susceptible to inhibition by protein kinase C. Eur J Immunol. 1999;29:3302-12 pubmed publisher
    Fcgamma receptors (FcgammaR) of guinea pig neutrophils were ligated and anti-Cbl immunoprecipitates prepared therefrom were assayed for the associated protein tyrosine kinase activity, which increased upon ligation of FcgammaR...
  75. Take H, Watanabe S, Takeda K, Yu Z, Iwata N, Kajigaya S. Cloning and characterization of a novel adaptor protein, CIN85, that interacts with c-Cbl. Biochem Biophys Res Commun. 2000;268:321-8 pubmed
    The c-Cbl protooncogene product is a prominent substrate of protein tyrosine kinases and is rapidly tyrosine-phosphorylated upon stimulation of a wide variety of cell-surface receptors...
  76. Haglund K, Shimokawa N, Szymkiewicz I, Dikic I. Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors. Proc Natl Acad Sci U S A. 2002;99:12191-6 pubmed
    ..b>Cbl proteins are major ubiquitin ligases that promote ligand-dependent polyubiquitination and degradation of receptor ..
  77. Oksvold M, Thien C, Widerberg J, Chantry A, Huitfeldt H, Langdon W. Serine mutations that abrogate ligand-induced ubiquitination and internalization of the EGF receptor do not affect c-Cbl association with the receptor. Oncogene. 2003;22:8509-18 pubmed
    ..We therefore tested the hypothesis that these mutations affect ligand-induced c-Cbl association with the receptor, leading to inhibited receptor ubiquitination...
  78. Davies G, Ettenberg S, Coats A, Mussante M, Ravichandran S, Collins J, et al. Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b. Oncogene. 2004;23:7104-15 pubmed
    b>Cbl proteins are ubiquitin protein ligases, which ubiquitinate activated tyrosine kinases and target them for degradation. Both c-Cbl and Cbl-b have an ubiquitin associated (UBA) domain at their C-terminal end...
  79. Thelemann A, Petti F, Griffin G, Iwata K, Hunt T, Settinari T, et al. Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells. Mol Cell Proteomics. 2005;4:356-76 pubmed
    ..kinase activity by erlotinib resulted in reduced phosphorylation of downstream signaling, for example through Cbl/Cbl-B, phospholipase Cgamma (PLCgamma), Erk1/2, PI-3 kinase, and STAT3/5...
  80. Caligiuri M, Briesewitz R, Yu J, Wang L, Wei M, Arnoczky K, et al. Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. Blood. 2007;110:1022-4 pubmed
    The CBL ubiquitin ligase targets a variety of activated tyrosine kinases (TKs) for degradation. Many TKs are mutationally or autocrine activated and/or often overexpressed at the mRNA and protein levels in acute leukemias...
  81. Shtiegman K, Kochupurakkal B, Zwang Y, Pines G, Starr A, Vexler A, et al. Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling. Oncogene. 2007;26:6968-78 pubmed
    ..Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants ..
  82. Miyake S, Mullane Robinson K, Lill N, Douillard P, Band H. Cbl-mediated negative regulation of platelet-derived growth factor receptor-dependent cell proliferation. A critical role for Cbl tyrosine kinase-binding domain. J Biol Chem. 1999;274:16619-28 pubmed
    The Cbl proto-oncogene product has emerged as a novel negative regulator of receptor and non-receptor tyrosine kinases...
  83. Bartkiewicz M, Houghton A, Baron R. Leucine zipper-mediated homodimerization of the adaptor protein c-Cbl. A role in c-Cbl's tyrosine phosphorylation and its association with epidermal growth factor receptor. J Biol Chem. 1999;274:30887-95 pubmed
    The 120-kDa proto-oncogenic protein c-Cbl is a multidomain adaptor protein that is phosphorylated in response to the stimulation of a broad range of cell surface receptors and participates in the assembly of signaling complexes that are ..
  84. Wong E, Fong C, Lim J, Yusoff P, Low B, Langdon W, et al. Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling. EMBO J. 2002;21:4796-808 pubmed
    ..herein that describes the functional implications of the direct association between human Sprouty2 (hSpry2) and c-Cbl, and its impact on the cellular localization and signalling capacity of EGFR...
  85. Kowanetz K, Szymkiewicz I, Haglund K, Kowanetz M, Husnjak K, Taylor J, et al. Identification of a novel proline-arginine motif involved in CIN85-dependent clustering of Cbl and down-regulation of epidermal growth factor receptors. J Biol Chem. 2003;278:39735-46 pubmed
    CIN85 is a multidomain adaptor protein implicated in Cbl-mediated down-regulation of receptor tyrosine kinases...
  86. Peschard P, Ishiyama N, Lin T, Lipkowitz S, Park M. A conserved DpYR motif in the juxtamembrane domain of the Met receptor family forms an atypical c-Cbl/Cbl-b tyrosine kinase binding domain binding site required for suppression of oncogenic activation. J Biol Chem. 2004;279:29565-71 pubmed
    ..RTK) for hepatocyte growth factor, initiates the recruitment of multiple signaling proteins, one of which is c-Cbl, a ubiquitin-protein ligase...
  87. 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...
  88. 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
    b>CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase...
  89. Park R, Izadi K, Deo Y, Durden D. Role of Src in the modulation of multiple adaptor proteins in FcalphaRI oxidant signaling. Blood. 1999;94:2112-20 pubmed
    ..that FcalphaR-mediated signals modulate a multimolecular adaptor protein complex containing Grb2, Shc, SHIP, CrkL, Cbl, and SLP-76...
  90. Yokouchi M, Kondo T, Houghton A, Bartkiewicz M, Horne W, Zhang H, et al. Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7. J Biol Chem. 1999;274:31707-12 pubmed
    c-Cbl plays a negative regulatory role in tyrosine kinase signaling by an as yet undefined mechanism...
  91. Fong C, Leong H, Wong E, Lim J, Yusoff P, Guy G. Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function. J Biol Chem. 2003;278:33456-64 pubmed
    ..that hSpry2 is tyrosine-phosphorylated upon stimulation by either FGFR or EGF and subsequently binds endogenous c-Cbl with high affinity...
  92. Gaston I, Johnson K, Oda T, Bhat A, Reis M, Langdon W, et al. Coexistence of phosphotyrosine-dependent and -independent interactions between Cbl and Bcr-Abl. Exp Hematol. 2004;32:113-21 pubmed
    b>Cbl is one of the major tyrosine-phosphorylated proteins in Bcr-Abl-expressing cells. A direct association between the SH2 domain of Bcr-Abl and tyrosine-phosphorylated Cbl has been demonstrated...