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Identification
HMDB Protein ID HMDBP07558
Secondary Accession Numbers
  • 13266
  • HMDBP09322
Name E3 ubiquitin-protein ligase CBL
Synonyms
  1. Casitas B-lineage lymphoma proto-oncogene
  2. Proto-oncogene c-Cbl
  3. RING finger protein 55
  4. Signal transduction protein CBL
Gene Name CBL
Protein Type Unknown
Biological Properties
General Function Involved in signal transducer activity
Specific Function Participates in signal transduction in hematopoietic cells. Adapter protein that functions as a negative regulator of many signaling pathways that start from receptors at the cell surface. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including PDGFA, EGF and CSF1, and terminates signaling
Pathways
  • Bafetinib Inhibition of BCR-ABL
  • BCR-ABL Action in CML Pathogenesis
  • Bosutinib Inhibition of BCR-ABL
  • Dasatinib Inhibition of BCR-ABL
  • Imatinib Inhibition of BCR-ABL
  • Nilotinib Inhibition of BCR-ABL
  • Ponatinib Inhibition of BCR-ABL
Reactions Not Available
GO Classification
Component
protein complex
organelle
membrane-bounded organelle
intracellular membrane-bounded organelle
nucleus
ubiquitin ligase complex
membrane-bound organelle
intracellular membrane-bound organelle
Function
ion binding
cation binding
metal ion binding
binding
catalytic activity
transition metal ion binding
zinc ion binding
ligase activity
protein binding
molecular transducer activity
signal transducer activity
ligase activity, forming carbon-nitrogen bonds
acid-amino acid ligase activity
ubiquitin-protein ligase activity
calcium ion binding
Process
cellular process
cell surface receptor linked signal transduction
intracellular signaling cascade
signal transduction
biopolymer metabolism
biopolymer modification
protein modification
ubiquitin cycle
protein ubiquitination
physiological process
metabolism
macromolecule metabolism
signaling
signaling pathway
cell surface receptor linked signaling pathway
cell communication
Cellular Location
  1. Cytoplasm
Gene Properties
Chromosome Location Chromosome:1
Locus 11q23.3
SNPs CBL
Gene Sequence
>2721 bp
ATGGCCGGCAACGTGAAGAAGAGCTCTGGGGCCGGGGGCGGCAGCGGCTCCGGGGGCTCG
GGTTCGGGTGGCCTGATTGGGCTCATGAAGGACGCCTTCCAGCCGCACCACCACCACCAC
CACCACCTCAGCCCCCACCCGCCGGGGACGGTGGACAAGAAGATGGTGGAGAAGTGCTGG
AAGCTCATGGACAAGGTGGTGCGGTTGTGTCAGAACCCAAAGCTGGCGCTAAAGAATAGC
CCACCTTATATCTTAGACCTGCTACCAGATACCTACCAGCATCTCCGTACTATCTTGTCA
AGATATGAGGGGAAGATGGAGACACTTGGAGAAAATGAGTATTTTAGGGTGTTTATGGAG
AATTTGATGAAGAAAACTAAGCAAACCATAAGCCTCTTCAAGGAGGGAAAAGAAAGAATG
TATGAGGAGAATTCTCAGCCTAGGCGAAACCTAACCAAACTGTCCCTCATCTTCAGCCAC
ATGCTGGCAGAACTAAAAGGAATCTTTCCAAGTGGACTCTTTCAGGGAGACACATTTCGG
ATTACTAAAGCAGATGCTGCGGAATTTTGGAGAAAAGCTTTTGGGGAAAAGACAATAGTC
CCTTGGAAGAGCTTTCGACAGGCTCTACATGAAGTGCATCCCATCAGTTCTGGGCTGGAG
GCCATGGCTCTGAAATCCACTATTGATCTGACCTGCAATGATTATATTTCGGTTTTTGAA
TTTGACATCTTTACCCGACTCTTTCAGCCCTGGTCCTCTTTGCTCAGGAATTGGAACAGC
CTTGCTGTAACTCATCCTGGCTACATGGCTTTTTTGACGTATGACGAAGTGAAAGCTCGG
CTCCAGAAATTCATTCACAAACCTGGCAGTTATATCTTCCGGCTGAGCTGTACTCGTCTG
GGTCAGTGGGCTATTGGGTATGTTACTGCTGATGGGAACATTCTCCAGACAATCCCTCAC
AATAAACCTCTCTTCCAAGCACTGATTGATGGCTTCAGGGAAGGCTTCTATTTGTTTCCT
GATGGACGAAATCAGAATCCTGATCTGACTGGCTTATGTGAACCAACTCCCCAAGACCAT
ATCAAAGTGACCCAGGAACAATATGAATTATACTGTGAGATGGGCTCCACATTCCAACTA
TGTAAAATATGTGCTGAAAATGATAAGGATGTAAAGATTGAGCCCTGTGGACACCTCATG
TGCACATCCTGTCTTACATCCTGGCAGGAATCAGAAGGTCAGGGCTGTCCTTTCTGCCGA
TGTGAAATTAAAGGTACTGAACCCATCGTGGTAGATCCGTTTGATCCTAGAGGGAGTGGC
AGCCTGTTGAGGCAAGGAGCAGAGGGAGCTCCCTCCCCAAATTATGATGATGATGATGAT
GAACGAGCTGATGATACTCTCTTCATGATGAAGGAATTGGCTGGTGCCAAGGTGGAACGG
CCGCCTTCTCCATTCTCCATGGCCCCACAAGCTTCCCTTCCCCCGGTGCCACCACGACTT
GACCTTCTGCCGCAGCGAGTATGTGTTCCCTCAAGTGCTTCTGCTCTTGGAACTGCTTCT
AAGGCTGCTTCTGGCTCCCTTCATAAAGACAAACCATTGCCAGTACCTCCCACACTTCGA
GATCTTCCACCACCACCGCCTCCAGACCGGCCATATTCTGTTGGAGCAGAATCCCGACCT
CAAAGACGCCCCTTGCCTTGTACACCAGGCGACTGTCCCTCCAGAGACAAACTGCCCCCT
GTCCCCTCTAGCCGCCTTGGAGACTCATGGCTGCCCCGGCCAATCCCCAAAGTACCAGTA
TCTGCCCCAAGTTCCAGTGATCCCTGGACAGGAAGAGAATTAACCAACCGGCACTCACTT
CCATTTTCATTGCCCTCACAAATGGAGCCCAGACCAGATGTGCCTAGGCTCGGAAGCACG
TTCAGTCTGGATACCTCCATGAGTATGAATAGCAGCCCATTAGTAGGTCCAGAGTGTGAC
CACCCCAAAATCAAACCTTCCTCATCTGCCAATGCCATTTATTCTCTGGCTGCCAGACCT
CTTCCTGTGCCAAAACTGCCACCTGGGGAGCAATGTGAGGGTGAAGAGGACACAGAGTAC
ATGACTCCCTCTTCCAGGCCTCTACGGCCTTTGGATACATCCCAGAGTTCACGAGCATGT
GATTGCGACCAGCAGATTGATAGCTGTACGTATGAAGCAATGTATAATATTCAGTCCCAG
GCGCCATCTATCACCGAGAGCAGCACCTTTGGTGAAGGGAATTTGGCCGCAGCCCATGCC
AACACTGGTCCCGAGGAGTCAGAAAATGAGGATGATGGGTATGATGTCCCAAAGCCACCT
GTGCCGGCCGTGCTGGCCCGCCGAACTCTCTCAGATATCTCTAATGCCAGCTCCTCCTTT
GGCTGGTTGTCTCTGGATGGTGATCCTACAACAAATGTCACTGAAGGTTCCCAAGTTCCC
GAGAGGCCTCCAAAACCATTCCCGCGGAGAATCAACTCTGAACGGAAAGCTGGCAGCTGT
CAGCAAGGTAGTGGTCCTGCCGCCTCTGCTGCCACCGCCTCACCTCAGCTCTCCAGTGAG
ATCGAGAACCTCATGAGTCAGGGGTACTCCTACCAGGACATCCAGAAAGCTTTGGTCATT
GCCCAGAACAACATCGAGATGGCCAAAAACATCCTCCGGGAATTTGTTTCCATTTCTTCT
CCTGCCCATGTAGCTACCTAG
Protein Properties
Number of Residues 906
Molecular Weight 99631.8
Theoretical pI 6.51
Pfam Domain Function
Signals
  • None
Transmembrane Regions
  • None
Protein Sequence
>E3 ubiquitin-protein ligase CBL
MAGNVKKSSGAGGGSGSGGSGSGGLIGLMKDAFQPHHHHHHHLSPHPPGTVDKKMVEKCW
KLMDKVVRLCQNPKLALKNSPPYILDLLPDTYQHLRTILSRYEGKMETLGENEYFRVFME
NLMKKTKQTISLFKEGKERMYEENSQPRRNLTKLSLIFSHMLAELKGIFPSGLFQGDTFR
ITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFE
FDIFTRLFQPWSSLLRNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRL
GQWAIGYVTADGNILQTIPHNKPLFQALIDGFREGFYLFPDGRNQNPDLTGLCEPTPQDH
IKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCR
CEIKGTEPIVVDPFDPRGSGSLLRQGAEGAPSPNYDDDDDERADDTLFMMKELAGAKVER
PPSPFSMAPQASLPPVPPRLDLLPQRVCVPSSASALGTASKAASGSLHKDKPLPVPPTLR
DLPPPPPPDRPYSVGAESRPQRRPLPCTPGDCPSRDKLPPVPSSRLGDSWLPRPIPKVPV
SAPSSSDPWTGRELTNRHSLPFSLPSQMEPRPDVPRLGSTFSLDTSMSMNSSPLVGPECD
HPKIKPSSSANAIYSLAARPLPVPKLPPGEQCEGEEDTEYMTPSSRPLRPLDTSQSSRAC
DCDQQIDSCTYEAMYNIQSQAPSITESSTFGEGNLAAAHANTGPEESENEDDGYDVPKPP
VPAVLARRTLSDISNASSSFGWLSLDGDPTTNVTEGSQVPERPPKPFPRRINSERKAGSC
QQGSGPAASAATASPQLSSEIENLMSQGYSYQDIQKALVIAQNNIEMAKNILREFVSISS
PAHVAT
GenBank ID Protein 126522478
UniProtKB/Swiss-Prot ID P22681
UniProtKB/Swiss-Prot Entry Name CBL_HUMAN
PDB IDs
GenBank Gene ID BC132733
GeneCard ID CBL
GenAtlas ID CBL
HGNC ID HGNC:1541
References
General References
  1. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  2. Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ: Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat Biotechnol. 2005 Jan;23(1):94-101. Epub 2004 Dec 12. [PubMed:15592455 ]
  3. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009 Aug 14;325(5942):834-40. doi: 10.1126/science.1175371. Epub 2009 Jul 16. [PubMed:19608861 ]
  4. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal. 2009 Aug 18;2(84):ra46. doi: 10.1126/scisignal.2000007. [PubMed:19690332 ]
  5. Beausoleil SA, Villen J, Gerber SA, Rush J, Gygi SP: A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol. 2006 Oct;24(10):1285-92. Epub 2006 Sep 10. [PubMed:16964243 ]
  6. Zhang Y, Wolf-Yadlin A, Ross PL, Pappin DJ, Rush J, Lauffenburger DA, White FM: Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules. Mol Cell Proteomics. 2005 Sep;4(9):1240-50. Epub 2005 Jun 11. [PubMed:15951569 ]
  7. Heibeck TH, Ding SJ, Opresko LK, Zhao R, Schepmoes AA, Yang F, Tolmachev AV, Monroe ME, Camp DG 2nd, Smith RD, Wiley HS, Qian WJ: An extensive survey of tyrosine phosphorylation revealing new sites in human mammary epithelial cells. J Proteome Res. 2009 Aug;8(8):3852-61. doi: 10.1021/pr900044c. [PubMed:19534553 ]
  8. Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B, Watts JD, Hood L, Aebersold R: Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry. Nat Methods. 2005 Aug;2(8):591-8. [PubMed:16094384 ]
  9. Wolf-Yadlin A, Hautaniemi S, Lauffenburger DA, White FM: Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5860-5. Epub 2007 Mar 26. [PubMed:17389395 ]
  10. Zheng N, Wang P, Jeffrey PD, Pavletich NP: Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell. 2000 Aug 18;102(4):533-9. [PubMed:10966114 ]
  11. Salomon AR, Ficarro SB, Brill LM, Brinker A, Phung QT, Ericson C, Sauer K, Brock A, Horn DM, Schultz PG, Peters EC: Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):443-8. Epub 2003 Jan 9. [PubMed:12522270 ]
  12. Yokouchi M, Wakioka T, Sakamoto H, Yasukawa H, Ohtsuka S, Sasaki A, Ohtsubo M, Valius M, Inoue A, Komiya S, Yoshimura A: APS, an adaptor protein containing PH and SH2 domains, is associated with the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis. Oncogene. 1999 Jan 21;18(3):759-67. [PubMed:9989826 ]
  13. Galisteo ML, Dikic I, Batzer AG, Langdon WY, Schlessinger J: Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation. J Biol Chem. 1995 Sep 1;270(35):20242-5. [PubMed:7657591 ]
  14. Deckert M, Elly C, Altman A, Liu YC: Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases. J Biol Chem. 1998 Apr 10;273(15):8867-74. [PubMed:9535867 ]
  15. Tang J, Sawasdikosol S, Chang JH, Burakoff SJ: SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9775-80. [PubMed:10449770 ]
  16. Holland SJ, Liao XC, Mendenhall MK, Zhou X, Pardo J, Chu P, Spencer C, Fu A, Sheng N, Yu P, Pali E, Nagin A, Shen M, Yu S, Chan E, Wu X, Li C, Woisetschlager M, Aversa G, Kolbinger F, Bennett MK, Molineaux S, Luo Y, Payan DG, Mancebo HS, Wu J: Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel inhibitor of antigen receptor signaling. J Exp Med. 2001 Nov 5;194(9):1263-76. [PubMed:11696592 ]
  17. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA: Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16899-903. Epub 2002 Dec 11. [PubMed:12477932 ]
  18. Vandenbroere I, Paternotte N, Dumont JE, Erneux C, Pirson I: The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2. Biochem Biophys Res Commun. 2003 Jan 10;300(2):494-500. [PubMed:12504111 ]
  19. Blake TJ, Shapiro M, Morse HC 3rd, Langdon WY: The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl was generated by a large truncation encompassing a proline-rich domain and a leucine zipper-like motif. Oncogene. 1991 Apr;6(4):653-7. [PubMed:2030914 ]
  20. Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC: The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science. 1999 Oct 8;286(5438):309-12. [PubMed:10514377 ]
  21. Lupher ML Jr, Songyang Z, Shoelson SE, Cantley LC, Band H: The Cbl phosphotyrosine-binding domain selects a D(N/D)XpY motif and binds to the Tyr292 negative regulatory phosphorylation site of ZAP-70. J Biol Chem. 1997 Dec 26;272(52):33140-4. [PubMed:9407100 ]
  22. Brdicka T, Imrich M, Angelisova P, Brdickova N, Horvath O, Spicka J, Hilgert I, Luskova P, Draber P, Novak P, Engels N, Wienands J, Simeoni L, Osterreicher J, Aguado E, Malissen M, Schraven B, Horejsi V: Non-T cell activation linker (NTAL): a transmembrane adaptor protein involved in immunoreceptor signaling. J Exp Med. 2002 Dec 16;196(12):1617-26. [PubMed:12486104 ]
  23. Wakioka T, Sasaki A, Mitsui K, Yokouchi M, Inoue A, Komiya S, Yoshimura A: APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. Leukemia. 1999 May;13(5):760-7. [PubMed:10374881 ]
  24. Kirsch KH, Georgescu MM, Shishido T, Langdon WY, Birge RB, 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 Feb 16;276(7):4957-63. Epub 2000 Nov 6. [PubMed:11067845 ]
  25. Liu J, Kimura A, Baumann CA, Saltiel AR: APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol Cell Biol. 2002 Jun;22(11):3599-609. [PubMed:11997497 ]
  26. Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ: Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature. 1999 Mar 4;398(6722):84-90. [PubMed:10078535 ]